Demographics, Assessment and Management of Pain in...

Demographics, Assessment andManagement of Pain in the ElderlyMellar P. Davis and Manish SrivastavaHarry R. Horvitz Center for Palliative Medicine, Cleveland, Ohio, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241. Demographics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

1.1 Cancer Pain in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241.2 Benign Pain in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251.3 Vitamin D Deficiency in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

2. Pain Management in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252.1 Unique Barriers to Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252.2 Consequences of Uncontrolled Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262.3 Physiological Changes with Aging that Influence Pain Management . . . . . . . . . . . . . 262.4 Principles of Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272.5 Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272.6 Biophysical and Biopsychosocial Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

3. Nonpharmacological Management of Pain in the Elderly . . . . . . . . . . . . . . . . . . . . . . . 294. Approaches to Pharmacological Management of Pain in the Elderly . . . . . . . . . . . . . . . . 29

4.1 Whether To Separate Malignant from Nonmalignant Pain . . . . . . . . . . . . . . . . . . . . 294.2 Principles of Good Prescribing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

5. Paracetamol (Acetaminophen) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306. NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

6.1 Gastrointestinal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316.2 Renal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316.3 Cyclo-Oxygenase-2 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

7. Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327.1 Prednisone and Prednisolone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327.2 Dexamethasone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

8. Agents Preventing Bone Resorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338.1 Calcitonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338.2 Bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

9. Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359.2 Other Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369.3 Opioid Classes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379.4 Opioids in Hepatic and Renal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429.5 Drug Interactions with Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

10.Pharmacological Treatment of Neuropathic Pain in the Elderly . . . . . . . . . . . . . . . . . . . . 4610.1 Antiepileptic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4710.2 Tricyclic Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4810.3 Local Anaesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4910.4 Other Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

11.Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

THERAPY IN PRACTICE Drugs Aging 2003; 20 (1): 23-571170-229X/03/0001-0023/$30.00/0

© Adis International Limited. All rights reserved.

Abstract The prevalence of pain increases with each decade of life. Pain in the elderlyis distinctly different from pain experienced by younger individuals. Cancer is aleading cause of pain; however, other conditions that cause pain such as facetjoint arthritis (causing low back pain), polymyalgia rheumatica, Paget’s disease,neuropathies, peripheral vascular disease and coronary disease most commonlyoccur in patients over the age of 50 years. Poorly controlled pain in the elderlyleads to cognitive failure, depression and mood disturbance and reduces activitiesof daily living. Barriers to pain management include a sense of fatalism, denial,the desire to be ‘the good patient’, geographical barriers and financial limitations.

Aging causes physiological changes that alter the pharmacokinetics and phar-macodynamics of analgesics, narrowing their therapeutic index and increasingthe risk of toxicity and drug-drug interactions. CNS changes lead to an increasedrisk of delirium.

Assessment among the verbal but cognitively impaired elderly is satisfactorilyaccomplished with the help of unidimensional and multidimensional pain scales.A comprehensive physical examination and pain history is essential, as well as areview of cognitive function and activities of daily living. The goal of pain man-agement among the elderly is improvement in pain and optimisation of activitiesof daily living, not complete eradication of pain nor the lowest possible drugdosages. Most successful management strategies combine pharmacological andnonpharmacological (home remedies, massage, topical agents, heat and coldpacks and informal cognitive strategies) therapies.

A basic principle of the pharmacological approach in the elderly is to startanalgesics at low dosages and titrate slowly. The WHO’s three-step guideline topain management should guide prescribing. Opioid choices necessitate an under-standing of pharmacology to ensure safe administration in end-organ failure andavoidance of drug interactions. Adjuvant analgesics are used to reduce opioidadverse effects or improve poorly controlled pain. Adjuvant analgesics (NSAIDs,tricyclic antidepressants and antiepileptic drugs) are initiated prior to opioids fornociceptive and neuropathic pain. Preferred adjuvants for nociceptive pain areshort-acting paracetamol (acetaminophen), NSAIDs, cyclo-oxygenase-2 inhibi-tors and corticosteroids (short-term). Preferred drugs for neuropathic pain includedesipramine, nortriptyline, gabapentin and valproic acid. Drugs to avoid are pen-tazocine, pethidine (meperidine), dextropropoxyphene and opioids that are bothan agonist and antagonist, ketorolac, indomethacin, piroxicam, mefenamic acid,amitriptyline and doxepin. The type of pain, and renal and hepatic function, alterthe preferred adjuvant and opioid choices. Selection of the appropriate analgesicsis also influenced by versatility, polypharmacy, severity and type of pain, drugavailability, associated symptoms and cost.

1. Demographics

1.1 Cancer Pain in the Elderly

Advanced cancer is common in the geriatricpopulation. Approximately 80% of patients withcancer experience pain,[1] and 55% of patients withcancer who are aged between 70 and 91 years are

functionally dependent or require assistance withactivities of daily living.[2] In addition, 23% ofthese patients are significantly depressed and 30%have fair to poor nutrition. Unlike younger pa-tients, 15% have underlying dementia.[2] Most aretaking multiple medications: 57% are on three ormore medications, 35% on five or more and 7% on

24 Davis & Srivastava

Adis International Limited. All rights reserved. Drugs Aging 2003; 20 (1)

ten or more.[2,3] The mean number of associatedcomorbid conditions is 3.5; these include cardio-vascular disease, congestive heart failure, chronicobstructive lung disease, diabetes, arthritis, hyper-tension and osteoporosis.[2] Many have chronicnonmalignant pain predating the cancer pain. Mostpatients with advanced cancer have multiple pains,with 67% of pains related to the underlying malig-nancy and 25% as a result of treatment. The mostcommon cancer-related pain arises from bone me-tastases. Neuropathic pain is experienced in 25–30% of patients.

1.2 Benign Pain in the Elderly

Age-specific morbidity rates for pain increaseper decade of life.[4] The prevalence of pain com-plaints among the elderly (aged >65 years) is ashigh as 67–80%.[1,4,5] Pain that is functionallyimpairing affects 45–80% of nursing home resi-dents;[6] half of these have daily pain. Commoncomorbid conditions causing pain include: lowback pain from facet joint arthritis; osteoarthritisand osteoporosis; previous bone fractures; rheu-matoid arthritis and polymyalgia rheumatica;Paget’s disease; peripheral neuropathies andneuropathic pain associated with stroke, shin-gles, diabetes, trigeminal neuralgia and nutri-tional neuropathies; peripheral vascular disease;and coronary artery disease.

1.3 Vitamin D Deficiency in the Elderly

Home-bound elderly, particularly those on anti-epileptic drugs or who malabsorb fat, are at highrisk for vitamin D deficiency, which causes deepmusculoskeletal and/or superficial light touchpain. One-third of nursing home patients confinedindoors for 6 months develop vitamin D defi-ciency, and as many as one-half of communitydwellers have reduced vitamin D levels.[3] A singledose of 100 000IU restores vitamin D levels andreduces pain.[3]

2. Pain Management in the Elderly

2.1 Unique Barriers to Pain Management

Cognitive impairment is one of the major bar-riers to assessment of pain in the elderly.[7,8] Mostelderly patients with cognitive impairment who areverbal can be assessed by a unidimensional painscale.[9] Cultural barriers among geriatric patientsfrom minority groups impair the ability to elicit apain history and determine pain severity becauseof language difficulties and culturally unique ex-pressions of pain.[8]

The elderly have fewer resources to pay for an-algesics, which results in failure to fill prescrip-tions. They usually have fixed incomes, lack Medi-care reimbursement for prescription medication inthe US, and experience formulary limitations bymanaged-care insurance companies and delaysfrom national mail-order pharmaceutical compa-nies. Many pharmacies have limited opioid avail-ability or do not carry opioids.[3,10]

Comorbidities complicate the management ofpain, particularly with disease-related decrease inend-organ function.[1,3] Additional barriers in-clude fatalism, denial, the philosophy of the ‘goodpatient’, geography (home-bound), fear of adverseeffects, fear of loss of independence, fear of ad-diction and fear of tolerance.[5,10-12] Some elderlypatients believe that pain medications may need tobe ‘saved’ until pain becomes intolerable or thatopioids are inappropriate for severe cancer painuntil death is imminent.[12] The fear of pain as anindicator of either serious disease or progressivecancer leads patients to under-report pain.[12]

Negative attitudes toward the elderly by youngprofessional caregivers may be sensed by olderpatients, which leads to avoidance. Depressionoften associated with pain in the elderly may leadto social isolation and failure to seek help withintractable pain.[10]

Physician-generated barriers include failure toassess patients fully because of lack of knowledgeand time.[13] Physicians frequently lack knowledgeof nonpharmacological approaches to pain man-agement and the pharmacology of analgesics.[14]

Demographics, Assessment and Management of Pain 25


Physicians fear opioid toxicity and fail in the pro-active prevention of opioid adverse effects, whichincrease with age.[15] Fear of opioid dependenceand legal scrutiny are also significant barriersamong inexperienced prescribers.[16]

2.2 Consequences of Uncontrolled Pain

Unrelieved pain increases the risk of cognitivefailure, specifically memory and attention span.[17]

Uncontrolled pain leads to diminished daytime en-ergies, loss of normal sleep architecture, less deepslow-wave sleep and more brief arousals throughthe night.[18] Sleep-deprived individuals havelower pain thresholds and thereby experiencegreater pain.[5,18] Uncontrolled pain is associatedwith loss of physical function, increased depres-sion and greater mood disturbances.[5,18] Memorycomplaints are not only related to depression withchronic pain, but also increase with the chronicityof pain.[19] Attention and the ability to performcomplex tasks are diminished with severe chronicpain.[20] Fear is frequently associated with pain,and the consequences of such fear are preventionof evaluation, intensification of pain, the promo-tion of functional disability and depression.[5] Poorpain control is an important determinant of qualityof life, especially among those in long-term carefacilities and near the end of life. The elderly canalso use pain for secondary gain.[3] Finally, thereis increased healthcare expenditure associatedwith unrelieved pain.[21]

2.3 Physiological Changes with Aging thatInfluence Pain Management

The elderly are more likely to have adverse ef-fects from the pharmacological management ofpain, because the drugs used have a narrower ther-apeutic index as a result of reduced or impairedrenal and hepatic function compared with thatin younger patients. As a result, the elderly aremore sensitive to the analgesic properties and ad-verse effects of opioids because of age-associatedhepatic, renal and CNS pharmacodynamic alter-ations.[10]

Physiological changes with age include a de-creased cardiac index of 1% per year and reducedrenal function of 1% per year after the age of 50years, decreased hepatic blood flow, decreased he-patic mass, reduced hepatic mono-oxygenases andcytochrome enzymes with relative preservation ofconjugases, and decreased plasma protein binding.Hepatic metabolism is reduced by 30–40%.[22]

Such alterations in liver function increase oral bio-availability of certain opioids by reducing hepaticextraction.[22] Aging is also associated with in-creased body fat, which increases the volume ofdistribution of lipophilic medications and delaysboth elimination and the onset of drug action with-out changing serum concentrations. Age-relatedreduced volume of distribution increases plasmaconcentrations of hydrophilic drugs, which sec-ondarily increases drug diffusion to receptor sites.Polypharmacy due to multiple comorbidities in-creases the potential for pharmacokinetic andpharmacodynamic drug-drug interactions.

The elderly experience enhanced response toCNS-active medications.[22] Subcortical and cor-tical atrophy decreases receptor sites, receptoraffinity and synthesis of the neurotransmittersacetylcholine, dopamine, GABA and noradrena-line (norepinephrine). The elderly have a 28%reduction in cerebral blood flow. Neuronal lossis greatest in the neocortex and hippocampus,particularly in the region of the locus ceruleusand substantia nigra, and may influence pain. G-proteins, which are secondary mediators of theaction on many receptors, including opioid re-ceptors, have decreased coupling. There is re-duced catalytic activity of adenylate cyclase,which is also a secondary mediator of pain.[22]

Many of these changes predispose the elderly todrug-induced delirium and reduced drug toler-ance.[23] Overt delirium of any cause contributesto relative opioid resistance and uncontrolledpain.[24]

The expression of pain is altered with advancedunderlying dementia, even though the sensory reg-istration of pain is well preserved. Executive func-tions that govern the expression of pain are signif-



icantly reduced by dementia and cognitive failure,leading to atypical behaviours and reactions withpain.[12]

There is decreased saliva formation in the el-derly, which is further reduced by multiple drugsthat have anticholinergic properties; this can de-lay absorption of sublingual tablets and matrix-embedded medications.[22] Stomach acid produc-tion is reduced, though this does not appear togreatly influence drug absorption.[22] Peristalsis isreduced, increasing the risk of constipation, nau-sea and vomiting from opioids.[22] Fortunately,small-bowel absorption is not influenced to a sig-nificant extent by aging and is not rate limiting.[22]

Decrease in sympathetic innervation of jux-taglomerular cells within the kidney in the elderlyreduces aldosterone and renin release, leading to in-creased risk for hyperkalaemia, particularly withNSAIDs, by further reducing renin levels.[22] Theelderly are at increased risk for orthostatic hypo-tension with adjuvants such as tricyclic antidepres-sants or phenothiazines because of age-related di-minished baroreceptor response.

In summary, senescence causes pharmacoki-netic alterations that lead to higher concentrationsof drugs at receptor sites and delayed eliminationof lipophilic medications, as a result of increasedbody fat, and of hydrophilic medications, as a re-sult of reduced renal and/or hepatic function. Re-duced receptor sites are offset by pharmacokineticenhancement by both reduced volume of distribu-tion and reduced renal and hepatic clearance, par-ticularly with hydrophilic medications.[22] Com-pared with younger patients, the elderly develop ahigh frequency of unusual manifestations of ad-verse drug reactions, such as cognitive failure, lossof bladder or bowel control and anorexia.

2.4 Principles of Pain Management

The approach to chronic pain management istwo-fold: defining the underlying pathology ofpain and measuring its consequences, and treatingboth.[5] There are three principal elements to painmanagement:[25]

• comprehensive assessment;

• the use of combined nonpharmacological andpharmacological therapy;

• age- and organ function-adjusted pharmacol-ogy.The goal of pain management is pain reduction

associated with improved function, reflected inactivities of daily living, sleep and socialisation,and not necessarily complete absence of pain orthe use of minimal analgesic medication.

2.5 Assessment

Pain assessment tools for younger patientsare also likely to work in the elderly, even in thepresence of mild to moderate cognitive impair-ment.[7,26,27] The patient is the only reliable sourcefor pain assessment. He or she must describe thequality, location and nature of the pain and factorsthat relieve or worsen pain.[10,28] Unidimensionalscales, and sometimes multidimensional scales(McGill Pain Questionnaire or Brief Pain Inven-tory), are useful in patients who are verbal butcognitively impaired.[28] The McGill Pain Ques-tionnaire evaluates sensory, affective, evaluativeand miscellaneous pain experiences and providesadditional information to unidimensional scales.Pain is sometimes best characterised by patient-generated descriptors. A comprehensive pain his-tory seeks clues to the nature and aetiology and thetype of pain (nociceptive, neuropathic).[28] This isconfirmed by a good physical examination andcomprehensive neurological examination.

Pain is multidimensional and modulated bypersonal meaning and psychological state.[22,28]

Social context, belief and environment shape thepain experience.[29] Pain severity is modulatednegatively by depression, anxiety, delirium and thepatient’s psychological make-up (helplessness,anger, denial, fear, vulnerability and depend-ence).[25] Intensity, quality, time course, effect onfunctional status and personal meaning are uniqueto the individual and are not appreciably measuredby standard pain assessment tools.[11] Therefore,pain scales are limited in their ability to fully assesspain and should not be relied upon without a com-plete pain history or physical examination.[28]



Quantitative pain scales do provide a means ofsequentially assessing pain during pain manage-ment. Pain intensity scales cannot be used inter-changeably with pain relief scales, since there is apoor relationship between response as measuredby changes in the two scales.[26] Therefore, physi-cians should use only one unidimensional painscale in the frequent evaluation of pain responseand it should be consistently used throughout thecourse of treatment.[30] Pain scales that use a Likertscale may be easier for the elderly to comprehendthan numerical or visual analogue scales. Painmanagement is most successful when the under-lying cause for pain is known, which occasionallyrequires radiographs and ancillary studies. Treat-ment of pain should not wait until the results of thetests.[10]

There are additional assessments unique to theelderly: screening for depression, screening for cog-nitive impairment, assessment of activities of dailyliving, assessment of gait and balance, and assess-ment for visual and auditory impairment. Severelydemented patients may develop a particular patternof behaviour (grimacing, rocking, withdrawing,hyperkinesis, hypokinesis) as a unique pain signa-ture or behaviour, which may be recognised byclose caregivers.[5] In contrast, physiological res-ponses to pain, which include increased heart rateand decreased variability in respiration, are poorindicators of pain in the nonverbal patient.[29,31]

There are no reliable objective biological or phys-iological markers for the presence of pain.[10]

Pain diaries, which include the date, severity,time course during the day, and nonpharmacologi-cal and pharmacological treatments, are helpful inthe ongoing management of pain and evaluation ofresponse, although this should not lead to a preoc-cupation with pain.[3,10]

2.6 Biophysical and BiopsychosocialTherapies

The experience of pain is multifactorial, involv-ing not only the senses but also the cognition, af-fect, motivation and behaviour characteristics ofindividuals with chronic pain.[32] Recognition of

the cognitive, behavioural and sociocultural di-mensions of pain means that nonpharmacologicalmeasures that improve these components of painwill benefit patients with pain.[33] It is very difficultto separate the consequences of the pain experience(i.e. depression) from the sensory experience; bothare intertwined in the experience of suffering andboth require treatment.[34]

Depression is more common in patients withchronic pain than in healthy controls, either predat-ing or as a consequence of pain. Pain may kindledepression in predisposed individuals.[35] Thestrongest influence on pain, depression and copingis the meaning patients give to their pain.[32] Con-trol of depression and anxiety greatly improvespain, and identifying and developing appropriatecoping skills, adaptive skills and meaning may de-crease the crippling nature of chronic pain.[36]

Therefore, to manage chronic pain only in the con-text of a biophysical model rather than a bio-psychosocial experience will fail to fully managecancer-related and nonmalignant pain.[37]

The biopsychosocial model of pain emphasisesthe importance of nonpharmacological therapiesin combination with pharmacotherapy tailored tothe individual.[38] Such an approach requires aninterdisciplinary approach to nonmalignant andcancer pain in the elderly.[38] Cognitive, psycho-logical and pharmacotherapies are tailored both topatients and to pain characteristics.[39] Four factorshave been shown to predict the variability of out-come measures in chronic geriatric pain:[40]

• changes in patient activity;• changes in pain and related behaviour;• changes in constant pain; and• changes in attitude to pain centre goals.

Both physical and occupational therapy im-prove activities of daily living and adaptation tolimitations. Psychotherapy, broadly including re-laxation techniques, hypnosis, cognitive behaviou-ral techniques and biofeedback, improves skills forcoping with chronic pain.[41] Spiritual develop-ment and cognitive behavioural therapy reducethe suffering of the pain experience and improvecoping while reducing behavioural expressions of



pain.[42] Therefore, to successfully manage non-malignant or cancer pain in the geriatric patient,a multidisciplinary programme that enhances ac-tivities of daily living and improves healthy adap-tive and coping skills while using appropriate an-algesics has the greatest chance of success.[43-46]

3. Nonpharmacological Managementof Pain in the Elderly

The strategies least preferred by the elderly tomanage pain are most commonly prescribed byphysicians: medications, physical therapy and ex-ercise.[11] Preferred by the elderly are home reme-dies, massage, topical agents, physical modalitiessuch as heat and cold, and informal cognitive strat-egies (social gatherings, visiting neighbours, mu-sic, prayer and humour).[3,11]

Physical therapy may provide only time-limitedbenefits for chronic pain in some patients, and mayfail to provide additional adaptive coping skills ifnot continued at home by the patient. Psychother-apy is a helpful support in this regard. Geographi-cal barriers to physical therapy centre on transpor-tation to and from the medical facilities, with alimited number of family members available toprovide transport.[11] Exercise is usually avoidedby the elderly, particularly the frail, because of fearof falling, personal safety (sense of vulnerabilityin an unfamiliar environment), and limiting com-orbidities such as chronic obstructive lung diseaseand congestive heart failure.[11] Unconventionaltherapies are perceived to be low risk, whereasconventional therapies including medications areperceived as high risk, with associated adverseeffects that ultimately may cost patients their in-dependence.[11]

Transcutaneous electric nerve stimulation(TENS) is a low-risk procedure, as is ultrasound;both produce analgesia, although temporarily.TENS units have been used for spine-related pain,diabetic neuropathy, phantom limb pain and post-herpetic neuralgia, and occasionally for arthritis.[47]

Psychological methods include hypnosis, med-itation, relaxation, guided imagery, biofeedback,prayer and music therapy.[47] These need to be ap-

plied on the basis of interests, beliefs, skills andcognition. These behavioural therapies aim to en-hance healthy lifestyles and bolster coping be-haviours. Cognitive therapy can be combined withbehavioural approaches in a complementary fash-ion, facilitating pharmacotherapy.

4. Approaches to PharmacologicalManagement of Pain in the Elderly

4.1 Whether To Separate Malignantfrom Nonmalignant Pain

Malignant and benign pain are frequently con-sidered separately. Cancer pain is highly associ-ated with physical pathology, whereas nonmalig-nant pain is less so.[48] Cancer pain is seen more asbiophysical pathology than as a biopsychosocialexperience. Patients with cancer experience painthat overlaps in aetiology (nociceptive, neuro-pathic) with that seen in patients without the dis-ease. The anatomical, physiological and biochem-ical substrates and mechanisms of nociception arenot different between the two groups.[48] Chronicpain, whether nonmalignant or malignant, is mod-ulated by depression, anxiety, cognition, copingskills and meaning. Also, patients with cancer painfrequently have nonmalignant pain unrelated to theunderlying cancer or as a result of treatment, andthe two cannot be easily separated. These patientsusually have additional symptom burdens andstruggle with the finality of their existence. Theelderly benefit from a biopsychosocial model ofcare and multimodality pain management. As thepharmacology of treatment of both nonmalignantand cancer pain completely overlaps, there appearsto be no advantage in separating cancer and non-cancer pain.[48]

4.2 Principles of Good Prescribing

Clinicians must balance the risk and benefits ofdrug therapy and should follow the WHO three-step guideline whether the pain is nonmalignant ormalignant in origin.[49] Two major questions needto be addressed when ‘channelling’ a patient’sdrug course: does the drug bring a certain problem



to the patient, and does the patient bring a certainproblem to the drug?[50] Incremental goals for ob-taining pain relief are pain relief that allows forrestful sleep, pain relief at rest, and tolerable painwith activity. Improved function may occur to agreater extent than reduced pain intensity as mea-sured by unidimensional pain scales.[5]

Pain responses are better assessed by physicalfunctioning, psychosocial functioning, and im-proved mood and cognition.[5] A trial period is nec-essary and continuity of care is a must for assessingtreatment trials. Ineffective drugs are tapered anddiscontinued to minimise polypharmacy.

Pain relief with certain analgesics (particularlymorphine) occurs at lower doses with age, presum-ably because of delayed clearance or elimination.Final doses necessary for pain relief do not correl-ate with bodyweight or initial severity of pain. Inthe elderly, the duration of pain relief is longer thanpredicted by peak analgesic effect because of de-layed clearance and reduced volume of distribu-tion.[51,52] Therefore it is better to ‘start low and goslow’ with most analgesics.

Chronological age is not the same as physiolog-ical age, and this accounts in part for the wide inter-individual variation and unpredictable nature ofadverse effects as a result of divergent individualpatient therapeutic indexes. Interindividual differ-ences exceed ethnic differences. This is furthercomplicated by the psychosocial and spiritual con-text of the experience of pain.[10] The proper use ofadjuvant analgesics reduces existing opioid ad-verse effects, widens therapeutic indexes and im-proves pain relief in patients with incomplete orsuboptimal pain relief from opioids.

The principles of good prescribing are based onthe following: known evidence-based analgesicbenefits; a wide therapeutic index; fewest potentialadverse drug effects; fewest potential drug inter-actions; treatment of several symptoms with onedrug; least cost burden; compatibility with patientcomorbidity and end-organ function; versatility(multiple routes of administration); and prescrib-ing limited to one drug per drug class. Factors in-fluencing adverse drug reactions are age, sex, race,

polypharmacy, dosage, duration of treatment,compliance and underlying end-organ function.[22]

5. Paracetamol (Acetaminophen)

Paracetamol (acetaminophen) is preferred toNSAIDs in the elderly because of its low gastroin-testinal and renal toxicity.[3,5] Paracetamol is not aperipheral anti-inflammatory agent but is centrallyacting, and in this sense is a weaker analgesic thancyclo-oxygenase (COX) inhibitors. It is well ab-sorbed and metabolised by glucuronidation andtherefore has few drug interactions.[5] There are noage-related reductions in paracetamol clearance.The elderly may prefer an elixir form. Dosagesabove 2.6 g/day are unlikely to produce furtheranalgesic benefit. Hepatic toxicity increases withdosages above 4 g/day, but can occur at lowerdosages with coexisting liver disease, fasting oralcohol consumption on a regular basis.[3] Long-term use of paracetamol can eventually lead torenal toxicity, particularly if combined withNSAIDs.[47]

6. NSAIDs

NSAIDs have a major role in the managementof acute and chronic pain syndromes associatedwith cancer or nonmalignant disease, particularlywith somatic or visceral nociceptive pain. NSAIDsreduce joint swelling, tenderness and stiffness andimprove physical function in inflammatory arthri-tis to a greater extent than in mechanical arthritis(osteoarthritis). The choice of NSAID depends on do-sage schedule, response, cost and physician as wellas patient preference and experience. Extended-release NSAIDs are preferred for chronic pain forthe sake of compliance, although this is offset byincreased renal dysfunction when compared withshort-acting NSAIDs. As-needed administrationis preferred, particularly for intermittent pain.NSAIDs should be used one at a time and shouldnot be combined with corticosteroids or paraceta-mol because of the significant risk for gastrointes-tinal toxicity, therapeutic redundancy and, in thecase of paracetamol, renal toxicity. Analgesia withNSAIDs occurs within 4 hours, much sooner than



the anti-inflammatory effects, which are not appar-ent for several days to weeks.[3]

6.1 Gastrointestinal Toxicity

Despite their known benefit, NSAIDs are alsoassociated with adverse effects, the prevalence ofwhich increases with age. NSAIDs in the elderlyproduce a higher risk of peptic ulcer disease, un-controlled hypertension, renal failure and worsen-ing congestive heart failure than in younger pa-tients.[10] Patients over the age of 60 years have a3–4% risk of severe gastrointestinal bleeding, andif there is a history of gastrointestinal bleeding, therisk is 9%.[10,27] Elderly women are at particularrisk because of a higher dose per bodyweight.[3]

Also, prevalence is increased in those with Heli-cobacter pylori gastritis.[3] The toxicity risk withNSAIDs is dependent on both dose and duration.An inverse relationship exists between duration oftherapy and gastrointestinal toxicity, supposedlybecause of mucosal adaptation.[3]

NSAIDs associated with less gastrointestinaltoxicity are etodolac, ibuprofen, nabumetone andmeloxicam, although confidence levels of safetyoverlap with those of other NSAIDs.[3] Routine useof indomethacin, ketorolac, piroxicam and mefe-namic acid is to be avoided because of increasedrisk of toxicity.[53] Approximately 40% of patientsdiscontinue NSAIDs because of gastrointestinalintolerance.[47]

The use of misoprostol, double-dosage hista-mine H2 antagonists and proton pump inhibitorsonly partially reduces the risk of gastrointestinaltoxicity, potentiates the risk for drug interactionsand adverse effects and does not significantlyreduce renal toxicity.[10] Alternatives in high-riskindividuals include non-acetylated salicylates,COX-2 inhibitors, low-dosage corticosteroids andlow-dosage opioids, depending on the clinical sit-uation.

6.2 Renal Toxicity

The renal toxicities of NSAIDs include revers-ible renal insufficiency, sodium and water reten-tion, hyperkalaemia, interstitial nephritis and acute

renal failure.[47] Fortunately, renal toxicity is notas common as gastrointestinal toxicity. Diuretics,ACE inhibitors and advanced age are major riskfactors for renal toxicity.[3] Renal dysfunction isusually reversible if recognised early and NSAIDsare withdrawn. Interstitial nephritis is rare butleads to permanent renal failure. Clinical factorsassociated with NSAID-induced renal toxicity arereduced effective circulating volume, diuretic use,congestive heart failure, cirrhosis, diabetes, infec-tion and pre-existing renal disease.[3]

Adverse renal reactions to NSAIDs are relatedto age over 75 years, congestive heart failure, de-hydration, history of peptic ulcer disease, historyof renal disease, hypertension, female sex and con-comitant use of diuretics.[47] Concurrent diureticsand NSAIDs lead to reduced renal blood flow, re-duced glomerular filtration rate and increased so-dium retention.[3] NSAIDs reduce renal prosta-glandin and renin secretion and may cause asudden rise in serum potassium while patients areon ACE inhibitors or potassium-sparing diuret-ics.[3] Elderly patients with preserved renal func-tion usually tolerate both long- and short-actingNSAIDs; however, long-acting NSAIDs producea small decrement in renal function if patients havepre-existing mild renal insufficiency.

Recommendations when prescribing NSAIDsare as follows: pretreatment measurement of elec-trolytes and creatinine; repeat electrolytes in 1–4weeks; start with low dosages and go slowly withtitration; consider ‘as-needed’ schedule if pain isonly mild or intermittent. Less frequent toxicitiesinclude anxiety, dizziness, tinnitus, drowsiness,confusion, bronchospasm in aspirin-sensitive indi-viduals, urticaria, pruritus and photophobia.[47]

6.3 Cyclo-Oxygenase-2 Inhibitors

Rofecoxib and celecoxib are the highly selec-tive COX-2 inhibitors available in the US (etori-coxib is available in Europe). Both rofecoxib andcelecoxib have an equal risk of adverse renalevents when compared with nonselective COX in-hibitors.[3] Neither significantly alters the pharma-cokinetics of warfarin or adversely alters platelet



function, and therefore there is a significantlylower risk for bleeding complication than nonse-lective agents.[3] Celecoxib is much more depend-ent on cytochrome P450 (CYP) for its metabolismthan is rofecoxib.[3]

Rofecoxib may be prescribed for individualswith aspirin-sensitive asthma and, unlike cele-coxib, can be used in patients with sulfa drug al-lergies and is less likely to lead to reactions in pa-tients with NSAID allergies.[3] Rofecoxib has anonset of action that is more rapid and more durablethan that of celecoxib.[3] Rofecoxib is administeredonce daily, which improves compliance. Therapywith either COX-2 inhibitor should start at thelowest dosage and be titrated slowly. Both cancerpain and nonmalignant pain respond to COX-2 in-hibitors; however, their use in cancer pain is notwell studied.

7. Corticosteroids

Corticosteroids are useful alternatives to NSAIDsin certain clinical situations. Corticosteroids aredisease-modifying and analgesic for patients withpolymyalgia rheumatica and reduce pain associ-ated with rheumatoid arthritis, although they arenot disease-modifying in this condition. Cortico-steroids reduce peritumoral swelling, oedema andpain associated with compressive neuropathies andcerebral metastases and are preferred in these situ-ations. Relief of pain and nausea occur in malig-nant bowel obstruction, pain from soft tissue tu-mour infiltration and cancer-associated visceralpain.[21]

Corticosteroids can replace NSAIDs for malig-nant bone pain in individuals who are at high riskfor NSAID-induced gastrointestinal toxicity, whohave renal dysfunction or who have several addi-tional symptoms that may respond to corticoste-roids (anorexia, nausea). The nonspecific benefitsof corticosteroids are improved appetite and moodand a feeling of well-being which, although it tendsto be of short duration (measured in weeks), maybe meaningful to patients.

Toxicity appearing shortly after starting corti-costeroids includes dysphoria, glucose intolerance,

hypertension, infection and psychosis.[5,21] Long-term adverse effects include accelerated cataracts,osteoporosis, aseptic necrosis of joints, and thin-ning of the skin with associated risk of skin tearsand bruising. Therefore, dosage should be reducedto the minimal effective level after maximum ben-efit has been achieved. Various administrationschemes can be used: dexamethasone 4–8mg twoto three times daily; methylprednisolone 16–32mgtwo to three times daily; or prednisone 20–40mgtwo to three times daily.[21] Epidural cord compres-sion is treated with doses as high as 100mg of dex-amethasone, resulting in analgesia within 24 hours.Corticosteroids can be given orally, intravenously,subcutaneously, rectally, intra-articularly, topi-cally and spinally.

Relative contraindications to corticosteroids in-clude HIV infection, recent intestinal anastomosis,uncontrolled congestive heart failure, severe renalimpairment, recent varicella infection, active orlatent oesophageal, gastric or duodenal ulcer, dia-betes, systemic fungal infections, ocular herpessimplex, myasthenia gravis, active or latent tuber-culosis, and concurrent use of NSAIDs.[21]

7.1 Prednisone and Prednisolone

Prednisone has nonlinear pharmacokinetics andprednisolone has linear pharmacokinetics, butthese differences are not used as a guide to deter-mining administration strategies.[54,55] Pharma-cokinetics and pharmacodynamics differ for bothagents depending on race and sex, but again thesedifferences are not clinically relevant.[56] In adults,regardless of age, response to prednisone andmethylprednisolone is not influenced by the kine-tics.[57] There is hepatic interconversion betweenprednisone and prednisolone. The oral bioavaila-bility of prednisolone is 62%, which is greater thanthat of prednisone.[58]

Combined use with proton pump inhibitorsdoes not influence prednisone or prednisoloneconcentrations.[59] Itraconazole inhibits methyl-prednisolone metabolism by blocking CYP3A4metabolism, thus delaying elimination.[60] Methyl-



prednisolone is more expensive in the US, and asa result prednisone is preferred.

Patients with hepatic or renal failure or renaltransplant, those older than 65 years, women tak-ing estrogen-containing oral contraception, andpatients taking ketoconazole have increased un-bound prednisone. Increased unbound concentra-tions results in a greater volume of distribution anddelayed elimination. Patients with hyperthyroid-ism or Crohn’s disease, individuals taking medica-tions that induce the CYP system and patients tak-ing enteric-coated prednisolone have decreasedplasma concentrations of prednisolone.[61]

7.2 Dexamethasone

The oral bioavailability of dexamethasone is61–65%,[62-64] with wide interindividual variationin bioavailability unrelated to age, sex or body-weight. Obesity increases lag time to absorptionand positively correlates with the area under theconcentration-time curve.[65] There is diurnal cy-clic variation in oral absorption, which is not dra-matic and not clinically relevant.[65] Dexametha-sone is 75% bound to albumin. Protein binding isreduced by 24% in uraemic patients, which in-creases bioavailability. Renal failure increasesdexamethasone clearance in part through reducedcirculating unbound drug.[66,67] The terminal half-life of dexamethasone is 4 hours.[68,69]

Dexamethasone is principally metabolised byCYP3A4 to an inactive metabolite. Liver dysfunc-tion reduces clearance by 53%.[70] Phenytoin, car-bamazepine and phenobarbital (phenobarbitone)induce CYP3A4 activity and increase dexametha-sone clearance. Dexamethasone in turn inducesCYP3A4 activity and may reduce drug concentra-tions of antiepileptic drugs. Alcohol may increaseor decrease dexamethasone clearance. For un-known reasons, dexamethasone clearance is de-layed by depression and improves with resolutionof depression.[66,71,72]

8. Agents Preventing Bone Resorption

8.1 Calcitonin

Calcitonin relieves pain due to excessive boneresorption. Pain from bone metastases, noncancer-associated osteoporosis and Paget’s disease mayrespond. Phantom limb pain is relieved by calcito-nin, independently of the effect of the drug on boneturnover.[21] Calcitonin is reported to amelioratemigraine headaches.[21] Adverse effects includelocal cutaneous reactions, gastrointestinal upsetand allergic reactions. Nausea occurs in 10% ofpatients and cutaneous flushing, particularly ofhands and feet, in 2.5%. Nasal sprays producerhinitis in 12%, general achiness in 10% and epi-staxis in 3.5%. Dosage is 8 IU/kg subcutaneouslyor intravenously every 6–12 hours; nasal spraydosage is 200 IU/day.[21]

8.2 Bisphosphonates

The bisphosphonates, of which three genera-tions are available, are analogues of pyrophos-phate. Structurally they have a P-C-P backbone,with potency related to the side chain attached tothe carbon located between the two phosphates.Bisphosphonates bind to hydroxyapatite crystals,preventing resorption directly and inhibiting os-teoclastic activity. Intermittent use prevents osteo-porotic complications. Pamidronic acid and nowzolendronic acid are indicated for cancer-relatedhypercalcaemia. Bisphosphonates have antitumouractivity in some cancers.[21] Pamidronic acid re-lieves pain associated with bone metastases andreduces opioid requirements by 30–50% of base-line. Pamidronic acid is approved for long-termmonthly administration in myeloma and breastcancer for reducing or delaying orthopaedic com-plications. Other solid tumours may benefit, al-though data are meagre.

Adverse effects include post-treatment arth-ralgias and fevers in a minority of patients; bothresolve after several days. Rare complications in-clude hypocalcaemia, hypokalaemia, hypophos-phataemia and hypomagnesaemia. The usual dos-age of pamidronic acid is 90mg intravenously



every 3–4 weeks; the dosage of zolendronic acid is4mg intravenously every 4 weeks.[21]

9. Opioids

Opioids are the drugs of choice for moderate tosevere pain unrelieved by NSAIDs (steps 2 and 3according to WHO guidelines). These recommen-dations are based on severity of pain, not type ofpain or whether the pain is related to cancer or isnonmalignant in origin. The potency of the variousopioids parallels opioid receptor affinity and clin-ical efficacy (the number of receptors needing tobe occupied before pain relief). For morphine, un-like fentanyl, analgesia does not correlate withplasma concentrations.[73] The ‘weak’ opioids co-deine and tramadol have ceiling effects, resultingin limited analgesia and dose-related adverse ef-fects despite dose escalation. Both tramadol and co-deine are converted to µ-agonists by CYP2D6.[74]

Patients receiving medications that block CYP2D6or who are CYP2D6 poor metabolisers fail to ex-perience analgesia with either of these opioids.[75]

Step 2 analgesics also consist of combinationsof opioids plus NSAIDs in a single formulation,which have a ceiling dose because of the NSAID.These are usually a convenient step 2 medicationand improve compliance. Alternatives to the opioid-NSAID combinations are separately administeredpotent opioids (morphine or oxycodone) andNSAIDs, tailoring the regimen to the patient’s in-dividual needs. Pentazocine produces neuropsy-chiatric toxicity and is to be avoided in the elderly,as is pethidine (meperidine) because of the seizurerisk from accumulation of its metabolite norpeth-idine. The mixed agonist-antagonists nalbuphine,

butorphanol and buprenorphine have a limitedrole in the management of pain, since they causewithdrawal reactions when given to patients tak-ing pure opioid agonists and also have a ceilingdose.[47] Propoxyphene should also be avoided inthe elderly because of the risk of neural and cardiactoxicity.

Scheduled doses of opioids are tailored to the painpattern of the patient, and formulaic approaches areto be avoided. There is no standard schedule thatfits all patients, particularly with incident pain.However, there are general guidelines for admin-istration.[75,76] Frail elderly patients need extendedadministration intervals or dosage reductions be-cause of delayed opioid (morphine) clearance.[3]

The use of extended-release opioids increasescompliance, and these drugs are used once stabledoses of normal-release opioids are established.Some physicians start with low doses of extended-release opioids and provide breakthrough normal-release opioids for interim pain. End-of-dose fail-ure is treated by increases in the regular dose withmaintained intervals, or by shortening the intervalsand maintaining the doses. Table I shows the routesof administration for the opioids used in this pop-ulation.

Patients require different opioid regimens forcontinuous baseline pain and incident pain.[76] Thedosage needed for breakthrough incident painmay be higher than predicted based on baselinemaintenance dosage. Alternatives for manage-ment of breakthrough or incident pain are patient-controlled analgesia, sublingual fentanyl or spi-nal opioids with or without bupivacaine orclonidine.[76] A standard initial breakthrough op-

Table I. Opioid routes of administration

Oral Rectal Sublingual Subcutaneous Spinal: intrathecal/epidural Intravenous

Codeine Codeine Fentanyl Fentanyl Fentanyl Fentanyl

Hydrocodone Methadone Methadone Hydromorphone Hydromorphone Hydromorphone

Hydromorphone Morphine Morphine Methadone Morphine Methadone

Methadone Oxycodone Morphine Morphine

Morphine Tramadol Oxycodone (Europe)

Oxycodone

Tramadol



ioid dose is usually the same as the 4-hourly dosewhen patients are on a 4-hour normal-release op-ioid schedule, and one-third of a 12-hourly dosegiven as needed at any time during a 4-hour inter-val when on a 12-hourly extended-release op-ioid.[76,77] The baseline dose of opioid is not ad-justed if baseline pain is under control; if incidentpain is still a problem, only the dose for incidentpain is increased. The incident-type breakthroughpain is then treated independently if it is signifi-cantly unrelieved with ‘usual doses’.

Normal baseline dosage titrations for chronicpain are 50–100% of the baseline dosage, depend-ing on the severity of pain. Baseline dosage in-creases of less than 25% are usually ineffective;dosage increments should be based on baselinedosage.[3] Some patients require asymmetricallong-term opioid administration because of worsepain at night. In some instances, opioid dosage re-quirements are higher with initial therapy thanwhen maintaining pain relief.[3]

Morphine is the opioid of choice whether painis nonmalignant or cancer pain. The starting oraldosage in opioid-naive frail elderly patients is5mg every 4–6 hours, with the same dose every2 hours as needed. In the ‘healthy’ (opioid-naive)elderly without comorbidities, 10mg every 4 hoursis a reasonable starting dosage.

9.1 Adverse Effects

Opioid adverse effects are independent of typeof pain (nociceptive or neuropathic) or whether theopioid is used for nonmalignant or cancer pain.

9.1.1 ConstipationTo prevent opioid constipation, prophylactic

laxatives and stool softeners are started at the ini-tiation of opioid administration. Bulk laxatives areineffective and should be avoided. It is importantto take adequate fluids to allow laxatives and stoolsofteners to work. Softeners such as docusate so-dium 100mg two to three times daily are combinedwith a stimulant laxative or osmotic laxative (bi-sacodyl, senna or sorbitol).[10] Dosage and sched-ule must be individualised and are not linearlyrelated to opioid titration. The elderly are particu-

larly at risk for constipation because of ancillarymedications (calcium channel antagonists, antichol-inergics), a sedentary existence and age-related re-duced bowel motility. Patients with ileostomies donot require laxatives, but those with colostomiesshould receive them.

9.1.2 SedationMild sedation and transient cognitive impair-

ment are common with initiation of opioids in theelderly; they usually do not require dosage reduc-tion, but rather reassurance that they usually re-solve after 3–4 days.[5] Poor pain control leads tocognitive failure independent of opioid use in olderindividuals, and impaired cognition is not a con-traindication to starting opioids.[75,78] If confusiondevelops with opioid treatment and is accompa-nied by hallucinations or myoclonus, opioid reduc-tion, opioid rotation, altered route of administra-tion, or discontinuation of adjuvants such astricyclic antidepressants are necessary, dependingon the clinical situation and pain control. If deathis imminent, opioids are usually not switched; hal-operidol is used for hallucinations and benzodia-zepines for myoclonus.

Driving is permissible when patients are takinglong-term stable dosages of opioid and cognitionreturns to baseline.[10] Both patient and familymembers should feel comfortable about operatinga motor vehicle. A test drive on an isolated countryroad with a relative may be prudent before resum-ing driving.

9.1.3 NauseaNausea from opioids arises from three potential

mechanisms: stimulation of the chemoreceptortrigger zone located in the postrema of the fourthventricle; vertigo from cochlear stimulation; andgastroparesis.[3] Nausea is not usually treated pro-phylactically, as it occurs in a minority of patients.Haloperidol is provided to those who are nause-ated, at a dosage of 0.5–1mg every 4 hours asneeded. If nausea is associated with vertigo, pro-chlorperazine 10mg orally or 25mg rectally every4–6 hours or transdermal scopolamine are reason-able choices. If early satiety is the cause, metoclo-pramide 10mg should be given every 4 hours. An-



tiemetics have a significant risk of inducing extra-pyramidal reactions and anticholinergic adverseeffects. Nausea usually abates spontaneously with-in several days. Persistent nausea requires dosagereduction, an alternative route of administration oropioid switch.[5,10]

9.1.4 Myoclonus and DeliriumMyoclonus is a common, usually mild, though

not well recognised adverse reaction to opioids. Itis frequently missed by physicians because of lackof understanding or recognition or because of itsmild nature in some patients. Myoclonus is not aharbinger of seizure; it originates from the spinalcord. Elimination of an offending antipsychoticagent (phenothiazines or tricyclic antidepressants)or opioid dosage reduction if pain is under controlis a logical first step.[75] If this fails to resolve my-oclonus and the patient remains in pain, an opioidswitch may be necessary. Clonazepam, valproicacid or gabapentin are used to treat myoclonuswhen patients cannot be switched or death is im-minent.[10]

There are several ways of managing confusionand delirium associated with opioids. Dosage canbe reduced if pain is under control. Benzodiaze-pines, ciprofloxacin and NSAIDs should be discon-tinued. An antipsychotic agent such as haloperidolis used if the patient is agitated. Opioid-sparingadjuvant analgesics allow for opioid reduction andmay resolve confusion or delirium. The choice ofadjuvant depends on the type of pain. Opioidswitch rather than opioid reduction is a reasonableoption if pain is not well controlled.[79] In our ex-perience, an opioid switch for delirium or confu-sion was necessary in 15% of patients, all of whombenefited from the switch. Changing the route ofadministration from oral to subcutaneous, intrave-nous, epidural or intrathecal reduces opioid dosageand allows for continued analgesia with resolutionof neuropsychiatric symptoms. Opioid antagonistssuch as naloxone do not reverse confusion, delir-ium or myoclonus and are not used. Delirium thatpredates opioid therapy is a contributing factor tocrescendo pain in cancer patients and needs to be

treated in addition to pain in order to improve paincontrol.[24]

9.1.5 Respiratory DepressionRespiratory depression is rare in opioid-naive

individuals if low starting dosages are used andtitrated properly. It occurs under various condi-tions:[3]

• rapid dosage escalation of opioid over a shortperiod;

• in patients who are placed on adjuvant analge-sics while opioids are titrated;

• after a successful neurolytic block performedwithout opioid dosage reduction;

• with rapid relief of pain by a single fraction ofradiation or rapid cord compression while on astable opioid dosage;

• with the onset of acute renal failure and opioidaccumulation.Patients who are sedated from opioids have mio-

sis.[3] Low doses of naloxone are used for suspec-ted opioid-induced respiratory depression. Becauseof the short half-life (30 minutes) of naloxone, con-tinuous infusion of naloxone is necessary if thepatient is taking sustained-release opioids or meth-adone.[76]

9.2 Other Considerations

9.2.1 Opioid Overlap with Conversion toSustained-Release or Transdermal FentanylSwitching from normal-release to sustained-

release morphine or oxycodone or from parenteralto sustained-release morphine requires a 2-houroverlap to maintain analgesia. Switching fromnormal-release opioids to a transdermal fentanylpatch requires a 12–18-hour overlap, and smalldoses of the normal-release opioid may be neces-sary to avoid withdrawal reactions as well as tomaintain analgesia.[3] When switching from con-tinuous subcutaneous or intravenous fentanyl to atransdermal patch of equivalent dose, a gradeddose reduction of the infusion over 12–18 hours isnecessary.

9.2.2 Opioid SwitchThe choice of a second opioid in an opioid

switch depends on the severity and type of pain,



the performance status of the patient, the nature ofassociated symptoms, regional alternative opioidavailability, versatile routes of administration, andend-organ (i.e. renal and hepatic) function. A 25–50% reduction in equianalgesic dose should beused when switching from one opioid to anotherexcept in the case of methadone, where 10% of theequianalgesic dose is recommended because of itslong half-life and intrinsic efficacy.[80]

9.2.3 Ideal Opioid for Acute Pain ManagementThe characteristics and administration strate-

gies of an ideal opioid for use in acute pain man-agement may differ from those for chronic painmanagement, and are independent of age. Impor-tant characteristics include:[73]

• rapid onset of action;• no pain at the injection site;• short duration of action;• inactive metabolites;• minimum risk of respiratory suppression;• wide therapeutic index;• limited drug interactions;• availability of a specific antagonist.

Small doses frequently administered without abaseline dose better reflect the pattern of acutepain with expected pain resolution within severaldays to a week.

9.2.4 Opioids and ToleranceSpecific tolerance to analgesia is rare and is

not age-related. Tolerance can be adaptive (condi-tioned) or pharmacological.[18] If pain increases ina patient with cancer who is receiving stable dosesof analgesics, the most likely cause is advancingcancer. Proposed mechanisms of tolerance includeG-protein modulation, subcellular alterations inkinases, sodium channel adaptation to opioid-induced neuronal hyperpolarisation, NMDA re-ceptor activation, and release of dynorphin.[76-79]

Chronic nonmalignant pain may be associatedwith tolerance more frequently than cancer pain,but this is not well studied.

9.3 Opioid Classes

9.3.1 Opioid Receptor PharmacologyThere are three classes of opioids: lipophilic

agents, the codeine family and morphine-relatedagents. Lipophilic agents, metabolised predomi-nantly by CYP3A4, include methadone and fen-tanyl; methadone is also metabolised by CYP1A2and CYP2D6. The codeine family includes hydro-codone, oxycodone, codeine and tramadol. Theseagents are hydrophilic and metabolised by CYP-2D6. Both codeine and tramadol require conver-sion of the parent drug to the active metabolite(morphine and desmethyl-tramadol), whereas theparent drugs oxycodone and hydrocodone are theprincipal analgesics. The morphine-related familyincludes morphine and hydromorphone, both ofwhich are glucuronidated and hydrophilic.

The main site of action of opioids is on µ(MOR), κ (KOR) or δ (DOR) opioid receptors inthe CNS. Access to the CNS is limited by proteinbinding, drug ionisation and hydrophilicity.[73]

Methadone is also analgesic through NMDA andmonoamine receptors.[80]

9.3.2 TramadolTramadol is one of the ‘weak’ opioids, acting

on MOR through the O-desmethyl-tramadol meta-bolite and as a monoamine reuptake inhibitorthrough the unmodified parent drug.[3] Potencycompared with morphine is 10 : 1.[81]

Equivalent doses of morphine have more ad-verse effects than tramadol, particularly constipa-tion, neuropsychiatric symptoms and pruritus.[81]

Laxatives, antiemetics and antipsychotics are re-quired less frequently with tramadol than withmorphine, which is an important consideration inthe elderly. Dosages can be increased to a maxi-mum of 400 mg/day. Dosage reduction is neces-sary in renal or hepatic failure; reductions are rou-tine for creatinine clearance less than 30 ml/minand/or age greater than 75 years.[5]

Adverse effects include constipation in 35%,dizziness in 5%, nausea in 5%, sedation in 3%,vomiting in 1% and sweating and headache in afew.[3] Analgesia is not experienced in CYP2D6poor metabolisers or with medications that block



CYP2D6. Conversion from tramadol to equi-analgesic doses of morphine in a poor metabolisercan lead to respiratory depression. There is littleadvantage of this agent over codeine except that itmay be less constipating. Tramadol is favoured incountries where access to potent opioids is se-verely limited.

9.3.3 Pethidine (Meperidine)Pethidine should simply be avoided in elderly

patients, and perhaps in all patients. Norpethidineaccumulates both with long-term use and in thosewith reduced renal function, and can lead to sei-zures. Norpethidine concentrations are also in-creased by classical antiepileptic drugs throughstimulation of CYP3A4.[3] Pethidine increases therisk of psychotomimetic adverse effects, falls andsedation in elderly patients when compared withother opioids.[3] Combinations of hydroxyzine andpethidine increase the risks of orthostatic symp-toms and sedation compared with each drug alone,and this further predisposes frail elderly patientsto falls and reduced cognitive function.

9.3.4 MorphineMorphine is well absorbed by mouth but highly

extracted (70%) by the liver, and as a result over-all oral bioavailability is 20–30% but with wideinterindividual variation.[76] Hepatic extraction ofmorphine is predominantly dependent on hepaticblood flow rather than glucuronidation rate.[82]

Serum protein binding is 30%, so reduced proteinbinding plays little part in drug kinetics. Morphineis glucuronidated by uridinediphosphoglucur-onosyltransferase (UGT) 2B7 to an inactive me-tabolite, morphine-3-glucuronide, which may beneurotoxic, and to an analgesic metabolite, mor-phine-6-glucuronide, which is 10–60 times morepotent than the parent drug but much more hy-drophilic.[76]

Both metabolites undergo enterohepatic circu-lation and are subsequently renally excreted. Some30% of morphine is conjugated at extrahepaticsites (brain, intestinal tract and kidney). The parentdrug and particularly morphine-6-glucuronide arequite hydrophilic and as a result have delayed hys-

teresis (peak plasma concentration to analgesia)compared with lipophilic opioids.

Morphine glucuronidation is not altered withage or dramatically influenced by hepatic fail-ure.[76] However, clinically, hepatic function andage better predict adverse effects than renal func-tion.[83] The age-related decrease in clearance ofmorphine and especially morphine metabolitesmeans that lower doses of morphine are usuallyadequate in the elderly compared with youngerpatients. Morphine is one of the safest opioids touse in hepatic failure, but its clearance (parent drugand metabolites) is quite sensitive to renal func-tion.

Morphine given rectally has a 1 : 1 equi-analgesic ratio to oral morphine, even though itspharmacokinetics are slightly different. Partial he-patic bypass results from the inferior and middlehaemorrhoidal vein drainage into systematic (ca-val) veins and bypassing the portal vein. As a re-sult, morphine concentrations are increased butmorphine-6-glucuronide concentrations are re-duced.

In our experience, the optimal ratio of intrave-nous or subcutaneous dose to oral dose of mor-phine is 1 : 3. We have found that subcutaneous-to-oral dose ratios of 1 : 2 are inadequate in asignificant number of patients

Topical morphine mixed in Intrasite®1 gel canbe applied to painful ulcerative malignant andnonmalignant skin wounds to relieve pain withoutsignificant systemic exposure and with a probablereduction in adverse events.[84-86] This may be par-ticularly appealing to the elderly, who fear mor-phine adverse effects. The mechanism of analgesiais through binding to peripheral opioid receptorson sensory afferent neurons.

Convenience is an important consideration tothe elderly. Controlled-release morphine allowsfor 8-, 12- or 24-hour administration intervals,which significantly improves compliance com-pared with 4-hourly administration. Improved out-comes from increased compliance may offset the

1 Use of tradenames is for product identification only anddoes not imply endorsement.



cost of sustained-release morphine. If a 4-hourlydosage schedule is preferred, a double dose can besafely given at bedtime, which allows the patientto sleep through the night undisturbed, althoughsustained opioid release at night would be pre-ferred. Routes of administration are oral, rectal,subcutaneous, intravenous, epidural and intrathe-cal as well as topical.

9.3.5 MethadoneCommercially available methadone consists of

two isomers: the L-isomer, which is analgesic, andthe D-isomer, which is a monoamine reuptake in-hibitor. Both isomers are NMDA receptor antago-nists.[87,88] The L-isomer is responsible for most ofthe adverse effects of methadone.

Oral bioavailability is 80%. Methadone is 90%protein bound, mostly to α1-acid glycoprotein,which is increased in inflammatory states, there-by delaying clearance.[88] It is metabolised byCYP3A4, CYP1A2 and CYP2D6. Methadone isquite lipophilic and readily crosses the blood-brainbarrier and oral mucosa. Plasma clearance is de-pendent on the patient’s phenotype for expressionof CYP isoenzymes and on concomitant drug ther-apy. Drug interactions occur with greater fre-quency with methadone than with morphine.

Wide interindividual variation in pharmacoki-netics results in a half-life that can range from8.5–58 hours.[88] Methadone induces its own me-tabolism with long-term administration, whichshortens its half-life. Pharmacokinetics are notsignificantly altered by renal failure, unlike thoseof most other opioids.[88]

Nonopioid analgesic receptor activities of me-thadone include NMDA receptor binding, mono-amine reuptake inhibition and DOR binding,which further complicate equianalgesic adminis-tration. A linear equianalgesic dose ratio ratherthan a single dose ratio with morphine complicatesopioid rotation. Equianalgesic conversions pro-portionally increase the dose ratios of morphine tomethadone when switching from progressivelyhigher doses of morphine. There are several dosagestrategies for methadone, including: (i) a sliding-scale equianalgesic dosage schedule given every 8

hours based on total daily oral morphine equi-analgesic dose; or (ii) an every-3-hours ‘as-needed’dose based on 10% of the daily morphine equiva-lent up to 30mg per dose.[80,88]

Drug accumulation occurs after several days ofas-needed administration and dosage intervals tendto lengthen at day 4–6 from the start. A twice- orthree-times-daily schedule may be possible after aweek. The total daily dosage is added on days 5and 6 and divided by 4, and this amount is givenevery 12 hours beginning on day 7 when using anas-needed dosage schedule. Some patients may re-quire more frequent dosing intervals, every 8 or 6hours. Doses should be adjusted accordingly.

Dose ratios do not differ between neuropathicand non-neuropathic pain.[89] All previous opioidsare usually stopped before starting methadone. Theoral-to-rectal bioequivalent dose ratio is 1 : 1and the intravenous- or subcutaneous-to-oral doseratio is 1 : 2.

Methadone is associated with a reduced inci-dence of visual hallucinations, myoclonus and con-stipation compared with morphine. Caution is ne-cessary when using methadone in elderly patientsbecause the unpredictably long half-life may beeven longer in the elderly. Methadone should beused with caution in individuals with somatisedexistential pain or who have a low tolerance toother opioids. Contraindications to methadone in-clude acute uncontrolled asthma and severechronic obstructive lung disease with carbon dio-xide retention. Methadone can be used in the rarepatient taking monoamine oxidase inhibitors(MAOIs).

Methadone is given orally, rectally, sublingu-ally, subcutaneously and intravenously. The costof methadone is one-tenth that of other sustained-release opioids and it is quite cost effective, partic-ularly for elderly patients with limited income.[88]

Methadone is a good second-line analgesic but re-quires some experience for comfortable prescrib-ing. It is an ideal analgesic for individuals with ahistory of substance abuse.



9.3.6 FentanylFentanyl has a rapid onset of action due to its

lipophilic properties, and a short duration of actionafter initial administration as a result of redistri-bution from spinal cord to peripheral fat, muscle,lung and gastrointestinal tract, all of which act asstorage sites. With continuous long-term adminis-tration, storage sites become saturated and thedrug accumulates.[82,89] Drug elimination is byCYP3A4, resulting in norfentanyl, which to all in-tents and purposes is a nonactive metabolite. Elim-ination by CYP3A4 is rate limiting. Since 85% offentanyl is protein bound, pharmacokinetics arealtered in low protein states.[89]

Analgesia is influenced by the plasma concen-trations of fentanyl, the type of pain, the age of thepatient, coadministered medications and interindi-vidual pharmacokinetics.[89] Fentanyl has a shorthysteresis, with a mean onset of analgesia 6 min-utes after peak plasma concentrations, in contrastto 15 minutes for parenteral morphine. Unlike mor-phine, fentanyl does not cause histamine releaseand is less likely to produce pruritus.[73] Also un-like morphine, plasma concentrations correlateclosely with analgesia.[73] Delayed ventilatory de-pression associated with long-term fentanyl treat-ment is due to reabsorption and redistribution ofsequestered drug from the gastrointestinal tract,muscle, fat and lung.[73,89] Hypotension and respi-ratory depression are potentiated when fentanyl iscombined with benzodiazepines.[73]

Fentanyl can be given sublingually, intrana-sally, subcutaneously, intravenously, transderm-ally, epidurally and intrathecally. Parenteral andepidural fentanyl are popular in the managementof acute postoperative pain because of quick on-set of action and short half-life. Indications fortransdermal fentanyl or sublingual fentanyl forbreakthrough are when the oral route is no longerfeasible (transdermal), compliance is a problem(transdermal), there is a need for rapid relief ofbreakthrough pain and incident pain (sublingual)or prior to dressing change (sublingual).[90-92]

Transdermal FentanylThe rate of absorption of the transdermal fen-

tanyl matrix patch is influenced by body tempera-ture, body fat and age. Absorption is delayed in theelderly. Subcutaneous fat acts as a secondary res-ervoir which dampens drug absorption and contri-butes to ongoing fentanyl release after removal ofthe patch. Drug can be released for as long as 24hours after removal of the patch. The transdermalreservoir is designed to deliver drug for 72 hours,which may be extended in frail elderly patients.Transdermal fentanyl should not be started inopioid-naive patients at dosages greater than 25µg/h and is not indicated for acute pain manage-ment.[3] Patches should not be placed over dam-aged skin. High body temperatures increase ab-sorption, which increases the risk of opioidtoxicity.

The fentanyl transdermal patch is an inflexiblesystem and is costly for the elderly. However,transdermal fentanyl is less constipating than mor-phine and produces less daytime drowsiness andless disruption to daily life. Transdermal deliveryassures compliance.[90]

Converting from morphine to fentanyl is a two-step process: step 1 calculates the dose in oral mor-phine equivalents at 4-hour intervals, and step 2selects the appropriate fentanyl transdermal patch.If the oral morphine equivalent dose is 5–20mg4-hourly, a 25 µg/h patch is selected; if 25–35mg4-hourly, a 50 µg/h patch; if 40–50mg 4-hourly, a75 µg/h patch; and if 55–65mg 4-hourly, a 100µg/h patch.[93] Intravenous morphine at approxi-mately 4 mg/h is equivalent to a 100 µg/h fentanylpatch.[80]

Sublingual FentanylSublingual (transmucosal) fentanyl is available

in a lozenge form designed for breakthrough pain.In a double-blind trial comparing transmucosalfentanyl with immediate-release morphine forcancer-associated breakthrough pain, fentanyl wasmore effective.[91] Sublingual administration par-tially bypasses hepatic and intestinal CYP3A4metabolism, which results in a peak fentanyl con-centration twice that of oral fentanyl.[69] Sublin-



gual bioavailability is 46–52%. Much of the sub-lingual drug is swallowed and metabolised by in-testinal and hepatic CYP3A4, which accounts inpart for the variable degree of analgesia with thesame dose.[94] The analgesic response is also influ-enced by saliva pH and individual level of hepaticand intestinal CYP3A4 activity.[94] As a result,there is no association between sublingual fentanyldose, morphine breakthrough dose or long-termopioid requirements, and the sublingual fentanyldose should be titrated independently of thearound-the-clock opioid regimen.[95] The meantime to onset of analgesia is 4 minutes, and theduration of analgesia is dose dependent: 159 min-utes for the 200µg dose and 220 minutes for the800µg dose.[92]

However, sublingual fentanyl is expensive anddifficult for the elderly to afford. Also, the xerosto-mia that accompanies aging makes it difficult forsome to dissolve the lozenge. Alternatively, theparenteral solution of fentanyl may be given sub-lingually for breakthrough pain or prior to painfuldressing changes. Doses of parenteral fentanylgiven sublingually range from 2.5–15µg, and thisform is much less expensive than the commerciallozenge (table II).[92] A 10µg sublingual dose ofthe parenteral form costs $US0.22, and relievesbreakthrough pain cost effectively.[92]

9.3.7 OxycodoneOxycodone is a MOR and KOR agonist with an

elimination half-life longer than that of morphine(3.7 vs 1.9 hours), and as a result the duration ofanalgesia tends to be longer than that of mor-phine.[96] The oral bioavailability of oxycodone is50–60%, with less interindividual variation thanmorphine.[97,98] Oxycodone is metabolised throughCYP2D6, but unlike codeine the parent drug is theactive analgesic; drugs that block CYP2D6 do notinfluence analgesia but prolong its duration bydelaying oxycodone elimination.[74,99] Oxymor-phone, a minor metabolite, is 14 times more potentthan oxycodone, but accounts for only 10% of oxy-codone metabolites and contributes little to anal-gesia. There is a claim of fewer adverse reactionswith sustained-release oxycodone compared with

equivalent doses of normal-release oxycodone, al-though this is controversial.[100]

The analgesic potency of intrathecal oxycodoneis markedly less than that of intrathecal mor-phine, which may be related to the distribution ofKORs.[97,101] Oxycodone is as poorly absorbedsublingually as morphine, as its lipid solubility isequivalent to that of morphine.[97,101] The oxyco-done-to-tramadol ratio is 1 : 8 and the morphine-to-oxycodone ratio ranges between 1 : 1 and1.5 : 1 because of the high variability in absorp-tion of morphine and unequal cross-tolerance be-tween morphine and oxycodone.[101-104] Oxyco-done produces greater analgesic cross-tolerancewhen switching to morphine from oxycodone thanfrom morphine to oxycodone.[105]

Women eliminate oxycodone more slowly (by25%) than men.[106] Drug elimination is affectedmore by sex than by age, which makes oxycodonean attractive opioid in the elderly.[106] The coef-ficient of variation in oral bioavailability foroxycodone as measured by the area under theconcentration-time curve is 33% less than that ofequivalent morphine doses.[107] Oxycodone hasthe same protein binding characteristics and vol-ume of distribution as morphine and, like mor-phine, its kinetics are not significantly altered inlow-protein states. Unlike methadone, proteinbinding of oxycodone is not influenced by acute-phase reactants such as α1-acid glycoprotein.[97]

Switching from morphine to oxycodone can im-prove morphine-associated neurotoxicity.[108]

Table II. Fentanyl cost analysis: cost per dose in US dollars($US-2002)

Dose (µg) Cost ($US)

Oral transmucosal lozenge 200 9.28

400 11.76

600 14.22

800 15.90

1200 17.89

1600 22.12

Fentanyl injection100 from 2mg vial 2.16



Oxycodone is as effective as morphine in therelief of cancer-associated pain and causes fewerdrug-related hallucinations than morphine.[79] Ithas been used for chronic nonmalignant pain asso-ciated with osteoarthritis. Adverse effects are sim-ilar to those of morphine, including nausea, som-nolence, dizziness, pruritus and headaches, and donot occur with greater frequency in the elderly thanin younger patients.[106] In the US, the oral formu-lation of oxycodone can be given rectally withequivalent bioavailability.[109,110] The parenteralsolution may also be given intranasally, with a bio-availability of approximately 46%.[109]

9.3.8 HydromorphoneHydromorphone, a hydrogenated ketone ana-

logue of morphine, is an MOR agonist and to alessor extent a DOR agonist.[111] There is biex-ponential absorption kinetics for oral and rectalhydromorphone, with an initial rapid phase of 2hours and a slow sustained release thereafter.[111]

Hydromorphone has a high first-pass clearance(62 ± 33%) with wide interindividual variation,similar to that of morphine. Oral bioavailabilityranges between 10 and 65%.[112-115] Rectal bio-availability is 33% with a range of 10–66%.Plasma concentrations appear to correlate withanalgesia in experimental trials, although thisrequires confirmation.[113] The oral-to-parenteralbioequivalent ratio is 5 : 1 but ranges between3 : 1 and 9 : 1.[111] Hydromorphone is slightlymore lipophilic than morphine.

Hydromorphone is glucuronidated to hydro-morphone-3-glucuronide and hydromorphone-6-glucuronide by conjugases and reduced tohydromorphinone by ketone reductase.[111] Themetabolites hydromorphone-6-glucuronide andhydromorphinone are analgesic but produced atlow concentrations, and do not contribute signifi-cantly to analgesia. Hydromorphone-3-glucuron-ide accumulates in renal failure with a ratio to theparent compound of 100 : 1 (normal ratio 27 : 1)and may induce neurotoxicity with renal fail-ure.[111,116,117] Like that of morphine, the clearanceof hydromorphone is mainly dependent on hepaticblood flow and, to a lesser extent, protein binding.

Clearance is reduced with reduced hepatic bloodflow.

The equianalgesic ratio between morphine andhydromorphone is 5 : 1, with some variation.[118]

Sublingual absorption is poor because of drugionisation at the usual saliva pH of 6. Drug inter-actions are similar to those with morphine, al-though not formally studied and rarely reported.The onset of action with oral administration is 38minutes, similar to that of morphine.[113] The hys-teresis of parenteral hydromorphone is 8 minutes,which is between that of fentanyl and morphine,reflecting relatively greater lipophilicity thanmorphine. There is incomplete analgesic cross-tolerance to morphine, and switching to hydromor-phone from morphine because of morphine-relatedadverse effects successfully controls pain and re-solves toxicity in 70–75% of cases.[111] Morphine-associated pruritus resolves by switching to hy-dromorphone.[119] Hydromorphone is more solublethan morphine, so large amounts can be given sub-cutaneously in small volumes, which is similar todiamorphine.[111] The adverse effects of hydromor-phone are comparable to those of morphine. Abusepotential is not greater than that of morphine, nordoes addiction occur more frequently with rapidadministration.[111,120]

Hydromorphone is as effective as morphine inthe relief of cancer pain and chronic nonmalignantpain.[121] Sustained-release hydromorphone is aseffective as normal-release morphine in control-ling pain.[122] Hydromorphone is given orally, rec-tally, subcutaneously, intravenously, epidurallyand intrathecally. Overall, hydromorphone has lit-tle advantage over morphine as a first-choice po-tent opioid.

9.4 Opioids in Hepatic and Renal Failure

Aging is associated with a gradual reduction inhepatic and renal function. Comorbid conditionsaccentuate and accelerate loss of renal and hepaticfunction and further complicate pain management.Analgesics must be carefully and cautiously pre-scribed in the elderly with hepatic and renal failure.The therapeutic index of most opioids is reduced



with end-organ failure. Opioid subclasses are dif-ferently affected by hepatic and renal failure andchoices can be made on the basis of an under-standing of altered pharmacokinetics of each op-ioid in patients with hepatic and renal fail-ure.[82,123]

The onset and time course of analgesia are re-lated to the concentration of the drug and the du-ration of drug concentration at receptor sites. Thetotal clearance of a drug is the sum of partialclearances (hepatic and renal). The contribution ofend-organ failure to drug clearance is related to thedominant site of metabolism or excretion and theparticular failing organ.[82] Reduced end-organfunction, which reduces drug clearance, in effectincreases the magnitude and duration of analgesiasuch that administration intervals are extended anddoses are reduced.

9.4.1 Hepatic FailureHepatic opioid clearance is dependent on he-

patic blood flow, residual hepatic enzyme capac-ity, degree of plasma protein drug binding, hepaticextraction ratio and shunting (portal and in-trahepatic).[82] With extensive hepatic extraction(first-pass clearance), drug metabolism is predom-inantly dependent on hepatic blood flow. Drugclearance is reduced by both intra- and extrahep-atic shunting and reduced hepatic blood flow,which increases oral bioavailability.[82]

When hepatic extraction is low, metabolism de-pends on both residual enzyme capacity (mono-oxygenases or conjugases) and drug protein bind-ing. Reduced drug binding increases the volumeof distribution and drug concentrations at recep-tor sites and increases elimination without increas-ing plasma concentrations; drug half-life is pro-longed.[82]

MorphineThe half-life of morphine is increased from 2–4

hours in severe hepatic dysfunction. Oral bioavail-ability increases as a result of shunting and reducedhepatic blood flow. This is counterbalanced by anincrease in extrahepatic glucuronidation. Bilirubindisplaces morphine from binding sites but this isnot clinically significant because morphine has

low protein binding.[82] In severe hepatic failure,drug half-life is doubled and oral bioavailabilityincreased. Morphine is one of the safest opioids touse in cirrhosis and hepatic failure.

MethadoneThe pharmacokinetics of methadone are rela-

tively unaltered in mild to moderate cirrhosis. Insevere hepatic disease, protein binding is reducedand the volume of distribution increased, produc-ing new stable plasma concentrations and in-creased tissue concentrations.[82] Long-term al-cohol consumption stimulates CYP3A4, whichincreases methadone clearance and offsets im-paired methadone clearance.[82] The kinetics ofmethadone are relatively unchanged except in se-vere disease.

FentanylFentanyl disposition is relatively unaffected by

mild to moderate hepatic disease. However, elim-ination is prolonged from 3.5–8.7 hours when he-patic blood flow is severely reduced, as demon-strated by aortic cross-clamp pharmacokineticstudies during aortic aneurysm repair. It may beassumed that half-life will be prolonged in severehepatic disease because of reduced hepatic bloodflow and reduced CYP3A4 enzyme activity.[82]

OxycodoneThe elimination half-life of oxycodone is sig-

nificantly prolonged in hepatic failure because ofdecreased CYP2D6 activity, which does not havethe hepatic reserve of CYP3A4, or glucuronida-tion. CYP2D6 is extremely rate limiting and easilysaturated and is only a small fraction of the entirehepatic cytochrome enzyme system.[74] The meanhalf-life in end-stage liver disease (before livertransplant) is 13.9 (range 4.6–24.4) hours; the half-life of oxycodone is normally 3.4 (range 2.6–5.1)hours. In severe liver disease, oxycodone accumu-lates if a standard 4-hour dosage schedule is main-tained.[124] Morphine, fentanyl and perhaps meth-adone are preferred over oxycodone in severe liverdisease.



Opioids That Should Be Avoided in Hepatic FailureThe following opioids should not be used in

liver disease: codeine, tramadol, dextropropoxy-phene, pethidine and pentazocine. Both codeineand tramadol have reduced conversion to the anal-gesic metabolite. Dextropropoxyphene has a sig-nificant risk of causing hepatic toxicity. Pethidineis converted to norpethidine, which accumulatesin liver failure. Pentazocine has an increased riskof neurotoxicity and confusion in patients withend-stage liver disease.[82]

9.4.2 Renal FailureRenal failure can affect both the metabolism

and elimination of opioids or their metabolites. Re-duced elimination and prolonged half-life of inac-tive metabolites are clinically irrelevant, but pro-longed elimination of active opioids or their activemetabolites leads to prolonged analgesia and in-creased opioid adverse effects.

CodeineCodeine is principally metabolised to codeine-

6-glucuronide. Demethylation of codeine producesmorphine, which accounts for 10% of codeine me-tabolites. The half-life of codeine in patients withrenal failure is markedly prolonged to 18.7 ± 9hours compared with 4 ± 0.6 hours in healthy indi-viduals. Codeine produces sedation in renal failureif doses are not reduced or administration intervalsprolonged.[125]

MorphineMorphine clearance is slightly prolonged by

renal failure, presumably because of reducedrenal glucuronidation. However, elimination ofthe potent MOR agonist metabolite morphine-6-glucuronide is significantly prolonged. An in-crease in plasma concentration of this metaboliteprolongs analgesia. A linear relationship existsbetween creatinine clearance and renal clear-ance of glucuronide metabolites.[125] CNS con-centrations of morphine-6-glucuronide are repor-ted to be 15 times greater in patients with renalfailure than in healthy individuals.[125] Perito-neal dialysis does not improve morphine-6-glu-curonide clearance. Haemofiltration and haemo-

dialysis reduce morphine plasma concentrationsby 75% and 48%, respectively.[125] Morphinedoses need to be significantly reduced in renal fail-ure.

FentanylIt has been assumed that renal failure does not

influence fentanyl pharmacokinetics, since fen-tanyl is metabolised to an inactive metabolite bythe liver and norfentanyl is not a significant anal-gesic even though it accumulates with renal fail-ure. However, renal CYP3A4 accounts for some ofthe extrahepatic metabolism of fentanyl and maycontribute to elevated fentanyl concentrations withrenal failure.[126] In addition, uraemia reduces he-patic metabolism of certain drugs with high hepaticextraction ratios.[127] Binding of fentanyl to albu-min and α1-acid glycoprotein is reduced by renalfailure, further affecting its volume of distributionand elimination. Variation in clearance rates forfentanyl increases from 40–68% in individualswith renal failure, resulting in less predictable doseselection. Blood urea nitrogen levels above 60mg/dl are associated with reduced fentanyl elimi-nation.[127] Renal failure has been associated withprolonged respiratory depression if fentanyl dosesare not reduced.

MethadoneMethadone does not have known neuroactive

metabolites. Renal excretion accounts for 20% ofthe drug. However, pharmacokinetics are not sig-nificantly altered in renal failure.[88] Some authorsdo suggest a 50% dose reduction in severe renalfailure.[125]

HydromorphoneHydromorphone clearance is not affected by

modest renal dysfunction. Switching from mor-phine to hydromorphone for morphine-induced ad-verse effects as a result of renal impairment bringsimprovement in 80% of patients.[128] On the otherhand, myoclonus, hallucinations, agitation andconfusion have been reported in patients with ad-vanced renal failure while receiving hydromor-phone, indicating that doses need to be reduced.[129]



In summary, methadone and hydromorphoneare relatively safe in moderate renal failure.Methadone is relatively safe in severe renal failure.Elimination of codeine, fentanyl, oxycodone, mor-phine and morphine glucuronide is prolonged byrenal failure and doses need to be reduced or ad-ministration intervals extended. Doses of all op-ioids need to be reduced in patients with severerenal failure. Dialysis corrects morphine clearanceto a certain extent, depending on the type of renalreplacement therapy.

9.5 Drug Interactions with Opioids

Potential drug interactions (table III) are not acontraindication to drug combinations but requirecautious prescribing. We frequently take advan-tage of certain drug interactions to improve paincontrol (for example, morphine and adjuvant anal-gesics). The best known drug interactions occur asa result of induction or inhibition of CYP isoen-zymes.[130]

9.5.1 AntibacterialsErythromycin inhibits CYP3A4, reducing clear-

ance of alfentanil. Information about the influenceof erythromycin on the kinetics of other CYP3A4-dependent opioids is relatively sparse. The anti-fungal drug ketoconazole is a potent inhibitor ofCYP3A4 and reduces methadone clearance. Flu-conazole to a lesser extent delays methadone me-tabolism.[88] Rifampicin (rifampin) induces CYP-3A4 and increases methadone clearance. It alsoincreases morphine glucuronidation and morphineclearance. Oxycodone clearance is also increasedby rifampicin.

9.5.2 Histamine H2 AntagonistsCimetidine impairs hepatic CYP isoenzymes

and reduces hepatic blood flow, leading to delayedmorphine clearance.[76] Cimetidine increases theterminal half-life of fentanyl. Ranitidine binds tothe CYP system with one-tenth the potency of ci-metidine and has a reduced risk of impairing mor-phine clearance. Famotidine has little drug inter-action with the opioids.

9.5.3 Antiepileptic DrugsPhenobarbital and phenytoin reduce methadone

concentrations by 50% through induction ofCYP3A4, potentially causing opioid withdrawaldespite stable methadone dosages.[88] Carbamaze-pine does the same by inducing CYP3A4 activity.Thiopental (thiopentone) reduces the analgesia offentanyl and alfentanil and increases sedation as-sociated with both.[130] Carbamazepine, phenytoinand phenobarbital increase the neurotoxicity ofpethidine by accelerating the metabolism of theparent drug to norpethidine.[130]

9.5.4 BenzodiazepinesMethadone concentrations are increased by di-

azepam through competitive inhibition of drug me-

Table III. Drug interactions with opioids

Decrease concentrations Increase concentrations

MorphineKaolin (oral) Phenothiazines

Phenytoin Tricyclic antidepressants

Barbiturates Ranitidine (questionable clinicalsignificance)Carbamazepine

Oral contraceptives Cimetidine

Metoclopramide

Diclofenac(morphine-6-glucuronide but notmorphine)

MethadoneNevirapine Fluvoxamine

Ritonavir Fluoxetine

Phenobarbital(phenobarbitone)

Ketoconazole

Fluconazole

Carbamazepine Alcohol (acute)

Risperidone Diazepam

Alcohol (chronic)

Cigarette smoking

Rifampicin (rifampin)

Fusidic acid

OxycodoneRifampicin Quinidine

Fluoxetine

Ketoconazole

Cimetidine

Ritonavir

FentanylThiopental (thiopentone) Cimetidine

Midazolam



tabolism. Dextropropoxyphene delays the clear-ance of alprazolam. Lorazepam and morphine areglucuronidated through the same isoenzyme(UGT2B7) and may theoretically compete for con-jugation.[76] Benzodiazepines added to opioids in-crease both sedation and the risk of delirium, andin general do not improve analgesia unless pain isdue to muscle spasm. Midazolam and diazepamaccentuate the respiratory depression caused byfentanyl and methadone.[130]

9.5.5 Tricyclic AntidepressantsMethadone increases desipramine concentra-

tions through competition at mutually shared CYPsites.[88] Amitriptyline and nortriptyline increasemorphine concentrations but do not influence oxy-codone clearance or metabolism.[130]

9.5.6 PhenothiazinesPhenothiazines potentially worsen the hypoten-

sion, respiratory depression and lethargy of op-ioids. The risk of hypotension is greater with thecombination of chlorpromazine and morphine thanwith either drug alone.[130] Phenothiazines may in-terfere with morphine metabolism.[76]

9.5.7 MetoclopramideMetoclopramide accelerates the absorption of

sustained-release morphine, resulting in increasedsedation.[76,130]

9.5.8 Selective Serotonin Reuptake InhibitorsSelective serotonin reuptake inhibitors are po-

tent inhibitors of several CYP isoenzymes, partic-ularly CYP3A4 and CYP2D6. Methadone clear-ance is delayed by fluvoxamine and oxycodonemetabolism is inhibited by fluoxetine.[88] The an-algesia of codeine and tramadol is lost, since theanalgesic metabolites of both drugs are not pro-duced.[74] The analgesia of oxycodone and hy-drocodone is preserved, since the MOR agonist isthe parent drug.

9.5.9 Monoamine Oxidase InhibitorsMAOIs used with either pethidine or dextropro-

poxyphene can precipitate serotonin syndrome.Morphine, methadone and fentanyl can be safelygiven with MAOIs.[130]

10. Pharmacological Treatment ofNeuropathic Pain in the Elderly

Individual variation in response to neuropathicpain is the rule, and doses of analgesics and adju-vant analgesics needed to achieve relief should beindividualised.[131] The goal is the least amount ofmedication necessary for pain control, and shouldbe accomplished through titration of one drug at atime.[131] Many patients require polypharmacy toachieve adequate relief, and sequential dosage ad-justments of individual medications are necessaryto avoid pharmacological confusion. A topicalagent with regional effects (e.g. topical lidocaine[lignocaine]) is preferred in the treatment of pe-ripheral neuropathies in the elderly because ofsafety and tolerability.[131] Long-term safety is aconcern in chronic nonmalignant pain, but is alesser concern for patients with a short survivalexpectancy. Adjuvant analgesics should be usedfirst, before opioids, particularly in nonmalignantpain. Classification of drugs for neuropathic painis as follows: topical analgesics, adjuvant analge-sics, opioids. Adjuvant analgesics are tricyclic an-tidepressants, antiepileptic drugs, local anaesthe-tics, α2-adrenergic agonists, corticosteroids andcapsaicin.

Common features of neuropathic pain are dam-age to thermonociceptive neuronal pathways bydisease, hyperalgesia and allodynia in areas of sen-sory deficit with subsequent development of sec-ondary hyperalgesia in nonaffected contiguousareas, and increased likelihood of a poor responseto opioids.[132] Nonmalignant neuropathic pain is acommon experience among the elderly, and isfound in one-third of patients with advanced can-cer pain. The fundamental principles of successfultreatment are as follows:• reduction of peripheral sensory input through

sodium channel blockade and prevention ofspontaneous neuronal depolarisation;

• pre- and postsynaptic blockade through NMDAinhibitors, opioid agonists or calcium channelantagonists;



• facilitation of inhibitory monoamine pathwaysthat descend through the periaqueductal grey(PAG);

• inhibition of neuroactive amino acid release(glutamate and aspartate);

• potentiation of the neuronal inhibiting aminoacids (GABA and glycine).Therefore, both antiepileptic drugs (sodium

channel blockers and GABA agonists) and tricy-clic antidepressants (PAG monoamine reuptakeinhibitors) are analgesics for neuropathic pain andare used before opioids, particularly if the pain isnonmalignant.[132]

Low dosages are started in the elderly (gaba-pentin 100–300 mg/day, valproic acid 250mg atnight, nortriptyline 10mg at night, desipramine10mg at night) and slowly titrated at 4–7 day in-tervals. Response to pain frequently occurs at sub-therapeutic dosages, for both anticonvulsant (val-proate, gabapentin) and antidepressant activity(nortriptyline, desipramine), and within days. Pa-tients with neuropathic cancer pain may requirelower dosages than patients with nonmalignantneuropathic pain (diabetes or post-herpetic neural-gia), although this is not well documented. Anti-epileptic drugs are selected for patients with car-diac conduction defects or arrhythmia, patients onanticholinergic medications, or those experiencingdry mouth, urinary retention, constipation or otheranticholinergic adverse effects.[10]

The administration frequency influences com-pliance with the drug regimen. Carbamazepinerequires multiple daily doses, as does gabapentin,whereas valproic acid and secondary amine tricy-clic antidepressants are given once nightly. Sev-eral symptoms may be treated simultaneously witheither class of medication, and drug selectionshould be based on comorbidities or associatedsymptoms such as bipolar affective disorder, uni-polar depression, colic, myoclonus, nocturnal uri-nary incontinence, seizures and tenesmus.

Combining tricyclic antidepressants and anti-epileptic drugs for refractory pain is often associ-ated with drug interactions, except with gaba-pentin. These pharmacokinetic drug interactions

occur through the CYP system. Opioids also re-lieve neuropathic pain in a significant number ofpatients and should be considered as a second-linemedication. Methadone, in particular, may be ef-fective, although this has not been formally con-firmed.[88] There is no analgesic cross-tolerancebetween tricyclic antidepressants and antiepilepticdrugs, and sequential trials with each class may besuccessful. Both are equally effective and reducepain in two-thirds of cases.[3]

10.1 Antiepileptic Drugs

10.1.1 CarbamazepineCarbamazepine relieves trigeminal neuralgia

and is one of several reasonable choices for dia-betic and cancer-related neuropathic pain. How-ever, carbamazepine does not reduce central (tha-lamic) mediated pain. Carbamazepine relievesburning and lancinating pain and allodynia. It isstructurally related to imipramine and for this rea-son should not be prescribed for patients with hy-persensitivity to tricyclic antidepressants. Carba-mazepine induces CYP3A4 and accelerates theclearance of multiple drugs, including methadoneand dexamethasone.[5,88]

Carbamazepine is usually given orally, but isalso well absorbed rectally. The initial dosage is100mg twice daily, with titration up to 1200mg/day depending on response and tolerability.Plasma drug concentrations do not correlate withanalgesia.

Carbamazepine should be avoided in patientswho are neutropenic. The elderly are particularlysusceptible to the adverse effects of carbamaze-pine, which include nystagmus, dizziness, diplo-pia, light-headedness, lethargy, cognitive changesand the syndrome of inappropriate antidiuretichormone secretion.[21] Because of its adverse ef-fect profile and drug interactions, carbamazepineis a second-line adjuvant, whereas gabapentin is apreferred first-line adjuvant.

10.1.2 GabapentinGabapentin relieves cancer-associated neuro-

pathic pain, diabetic neuropathy, post-herpeticneuralgia, reflex sympathetic dystrophy and tri-



geminal neuralgia.[21,133-135] Absorption from thegastrointestinal tract is mediated by a carrier sys-tem in the small bowel, and therefore the drugshould not be rectally administered. The half-lifecan exceed 24 hours in some elderly patients andsteady-state concentrations may take as long as 4–7 days to achieve.[5] Gabapentin has fewer druginteractions than carbamazepine and valproic acid.It is superior to amitriptyline in the treatment ofdiabetic neuropathy.[134]

The initial dosage of gabapentin is 100mg threetimes daily if renal function is normal, graduallytitrated to 3600 mg/day or even higher dependingon response. Increasing the dosage does not neces-sarily increase adverse effects. Bioavailability di-minishes with increasing dosage because of satu-ration of the gabapentin carrier. Administration ofmorphine with gabapentin increases gabapentinserum concentrations by reducing its renal clear-ance.[76] Gabapentin pharmacodynamically en-hances the analgesic effects of morphine.[134] Dos-age reduction is necessary for patients with renaldysfunction. Doses are as low as 100–300mg afterdialysis in patients on intermittent renal dialysis,but must be individually determined.

The adverse effects of gabapentin are somno-lence, ataxia, fatigue, tremor, diplopia and nystag-mus. Gabapentin is available only for oral admin-istration. Cost is a major drawback; otherwisegabapentin is ideal for neuropathic pain.

10.1.3 Valproic AcidValproic acid enhances GABA synthesis and

prevents GABA degradation.[136,137] Besides neu-ropathic pain, valproic acid relieves migraineheadaches and cluster headaches.[137,138] It reducesneuropathic pain associated with advanced cancerin 55% of patients at dosages of 200–600mg twicedaily.[139] Valproic acid is less expensive thangabapentin, does not interact with opioids, partic-ularly methadone, and differs from classical anti-convulsant medications in that it does not induceCYP3A4 activity.[88]

Valproic acid modestly inhibits mono-oxygen-ases, UGTs and epoxide hydrolase, but has fewerdrug-drug interactions than classical antiepileptic

drugs.[140,141] Hepatic toxicity associated withvalproic acid is due to 4-ene-valproic acid forma-tion by CYP2B1.[142,143] Valproic acid is largelyglucuronidated. Plasma concentrations of amitri-ptyline and nortriptyline are increased 42% byvalproic acid; reduction of the dosage of these twoantidepressants may be necessary if they are com-bined with valproic acid.

The initial dosage of valproic acid is 250mg atnight for individuals aged over 65 years and 500mgat night for those aged under 65 years. Valproic acidis taken orally, rectally and intravenously. In ourexperience, oral valproic acid is cost effective with-in hospice (capitated) reimbursement plans. Val-proic acid needs to be administered less frequentlythan gabapentin, and is more versatile in terms ofadministration routes than gabapentin.

10.1.4 LamotrigineLamotrigine blocks sodium channels and in-

hibits release of glutamate in the CNS. Very littleis known about its benefits in cancer pain, butit reduces phantom limb pain, AIDS-associatedneuropathy, trigeminal neuropathy, poststrokepain and painful diabetic neuropathy.[132] Thereare large interindividual differences in the phar-macokinetics of lamotrigine as well as the analge-sia obtained. Lamotrigine is a weak inducer ofUGTs, but has fewer drug interactions than otherantiepileptic drugs except for gabapentin. Adverseeffects are ataxia, incoordination, blurred vision,diplopia and, rarely, cutaneous reactions, particu-larly when doses are rapidly titrated or the drugis combined with valproic acid.[21]

The initial dosage of lamotrigine is 50 mg/dayfor 14 days, then 50mg twice daily for 14 days, thenincreased by 100mg per day each week to a maxi-mum dosage of 600 mg/day. In general, dosagesrange between 50 and 400 mg/day. Lamotriginecan be administered orally or rectally.[21] Furtherstudies are necessary before it becomes a standarddrug for neuropathic pain.

10.2 Tricyclic Antidepressants

Tricyclic antidepressants facilitate noradrena-line and serotonin neurotransmission in the PAG



by inhibiting monoamine reuptake. They are alsosodium channel blockers.[21] Neuropathic painassociated with cancer and diabetes, and post-herpetic neuralgia, are relieved by several tricyc-lic antidepressants.[132] Pain reduction occurs in57–65% of these patients.[3] Responses are seenwith amitriptyline dosages as low as 25mgdaily.[144] Neuropathic pain usually responds toone-third to one-half of the usual antidepressantdosage and has an onset of action as early as 3–10days, although longer duration of treatment andhigher dosages are necessary in some patients.[3]

A dose-response relationship is seen between 25and 75 mg/day, but also an increased risk for ad-verse effects.[144,145] Therapeutic antidepressantblood concentrations are 50–300 µg/L, but thereis no clear therapeutic plasma concentration forneuropathic pain.

Tricyclic antidepressants are lipophilic andhighly protein bound and distribute widely tobrain, liver, lung and heart.[146] Plasma concentra-tions peak by 2–8 hours, and the drugs undergoextensive first-pass hepatic clearance. Imipramineis metabolised to desipramine and amitriptyline tonortriptyline, and these metabolites are subse-quently conjugated to glucuronic acid.[146] The sec-ondary amines desipramine or nortriptyline con-tribute to the analgesia of the parent drug and areeven more lipophilic.[146] The half-life of the sec-ondary amines is twice that of the parent tertiaryamine, and more than a week may be required toclear tricyclic antidepressants. These drugs aremetabolised more slowly by individuals over theage of 60 years and in those receiving medica-tions that competitively or noncompetitively blockCYP metabolism. Amitriptyline dosages correlatewith CYP2D6 phenotype.[74] Dosage adjustmentsare needed according to age and polypharm-acy.[146]

There is little analgesic cross-tolerance be-tween the various tricyclic antidepressants. Thesecondary amines are preferred because of feweranticholinergic adverse effects, fewer associatedfalls in the elderly, less mental cloudiness and re-duced risk for orthostatic hypotension. Amitripty-

line and its demethylated metabolite nortriptylineincrease plasma morphine concentrations and de-lay morphine clearance.[76] The long half-life of allfour tricyclic antidepressants allows for once-dailyadministration.

Tricyclic antidepressants should be used cau-tiously in patients with closed angle glaucoma,benign prostatic hypertrophy, urinary retention,constipation, cardiovascular disease or second andthird degree heart block, conduction defects orprolonged QT intervals, and severe liver disease.Gabapentin and valproic acid are preferred to tri-cyclic antidepressants in these patients becauseof fewer drug interactions, lack of potential ar-rhythmias, no constipation, dry mouth and otheranticholinergic adverse effects, and little risk forurinary retention and orthostatic hypotension. Sud-den withdrawal of tricyclic antidepressants mayproduce abdominal pain, anorexia, apathy, baddreams, diarrhoea, drowsiness, headaches, insom-nia, irritability, malaise, mania, movement disor-ders and profuse sweating.[21]

A single bedtime dose produces fewer adverseeffects and takes advantage of the sedative benefitsof tricyclic antidepressants. Paradoxically, in rarecircumstances, tricyclic antidepressants cause in-somnia, and if this occurs a single morning dose isgiven. Other benefits of tricyclic antidepressantsinclude relief of tenesmus and nocturnal urinaryincontinence.

Standard dosages are 10–25mg at night in theelderly, with dose increments of 10–25mg every4–7 days until response. Once maximum pain re-lief is obtained, the dosage is maintained for 1month. A slow taper over 3–6 months is possiblethereafter without loss of benefit.[3] Most tricyclicantidepressants are given orally; doxepin may begiven rectally and amitriptyline intramuscularly.

10.3 Local Anaesthetics

Local anaesthetics relieve pain, regardless oftheir route of administration.[147] All are sodiumchannel blockers. Transdermal lidocaine relievesregional (dermatomal) pain only in the area inwhich it is placed. Mexiletine is an oral congener



of lidocaine.[101] The third local anaesthetic fre-quently used is bupivacaine, usually by neuroaxisinfusion in conjunction with an opioid.

Local anaesthetics are classified as amino estersand amino amides. Both types are lipid-solubledrugs with acid-base ionisation constant (pKa) val-ues that determine potency.[147] Local anaestheticsrapidly enter the CNS, with concentrations in thecerebrospinal fluid usually 90% of serum concen-trations.[147] Distribution of the drug consists oftwo phases: a rapid uptake in highly vascularisedtissues and a slow redistribution, biotransforma-tion and elimination phase.[147] Elimination is de-termined by hepatic and cardiac function for mostlocal anaesthetics, and by renal function for lido-caine.[147]

Local anaesthetics are useful in painful diabeticneuropathy, post-stroke pain, cancer-associatedneuropathic pain, radiculopathies, arachnoiditis,trigeminal neuralgia, phantom pain, thalamic painand lightning pains associated with tabes dor-salis.[21,148] Doses of lidocaine are 1–5 mg/kg in-fused over 5–35 minutes.[149] The initial dosage ofmexiletine is 150–200mg once to twice daily ti-trated to 1200mg. Usual dosages are 150–300mgevery 8 hours.[21] Responses to parenteral lido-caine have been used as a predictor of response toother sodium channel blockers such as mexiletineor carbamazepine.[114]

Contraindications to the use of local anaesthet-ics include heart block. A cardiologist should seethe patient if there are any cardiac conduction ab-normalities before placing patients on systemic li-docaine or mexiletine. All local anaesthetics arenegative inotropic agents and must be used cau-tiously in patients with decompensated heart fail-ure. Adverse effects include dizziness, gastrointes-tinal upset, headaches, irritability, nervousness andtremors. Gastrointestinal upset is minimised bytaking mexiletine with food and by slow dose titra-tion. Seizures have been reported with high dosesof mexiletine.[21]

Lidocaine is available parenterally or by trans-dermal patch, bupivacaine by the parenteral, epi-dural and intrathecal routes, and mexiletine orally.

10.3.1 Lidocaine (Lignocaine) Transdermal PatchThe lidocaine 5% patch releases drug that binds

to regional neuronal sodium channels in peripheraldamaged nerves, thereby reducing spontaneousimpulses. The patch itself, by protecting the skin,may prevent allodynia; the patch does not producesignificant serum concentrations.[131] The lido-caine patch does not work in centrally mediatedneuropathic pain syndromes or radicular pain fromspinal cord pathology. Adverse effects are mini-mal, but local skin irritation can occur.

The elderly are ideal candidates for the patchbecause of a low risk of adverse effects and druginteractions and improved compliance. Individualsneed to be instructed to place the patch in theproper location over the area of pain if it is to beeffective. Up to three patches are placed in the af-fected area for up to 12 hours per day.[131]

10.4 Other Agents

10.4.1 ClonidineClonidine is an α2-adrenergic agonist that in-

hibits noradrenaline release through binding to ad-renergic autoreceptors found on sympathetic neu-rons and additionally by increases in GABAA

receptor activity.[132] Clonidine adds to morphineanalgesia when taken orally or by transdermalpatch and is supra-additive when infused with mor-phine into the neuroaxis. Oral and transdermalclonidine relieves diabetic neuropathy and post-herpetic neuralgia. Neuroaxis clonidine with op-ioids is an acceptable combination for refractorycancer pain. Adverse effects include hypotension,constipation, dizziness, dry mouth, rebound hyper-tension, sedation and sexual dysfunction. Trans-dermal preparations can produce cutaneous ery-thema and pruritus.

The dosage of oral clonidine is 0.1mg twicedaily increased weekly by 0.3mg twice daily up toa maximum dosage of 2.4 mg/day depending onresponse and tolerability.[21] Transdermal clonid-ine needs to be changed weekly. Clonidine is avail-able orally, transdermally, epidurally and intra-thecally.



10.4.2 CapsaicinCapsaicin binds to vanilloid receptors, which in

time exhausts neuronal substance P, a major neu-rotransmitter of pain for C fibres.[132] Startingdoses are 0.025–0.075% topical cream appliedfive times daily. Initial administration producesburning, which is relieved when capsaicin is com-bined with topical anaesthetics. Compliance is achallenge because of multiple daily applicationsand worsening burning pain with initial use. Onthe other hand, there are few systemic adverse ef-fects. Cost is an issue.

10.4.3 BaclofenBaclofen is a GABAB analogue that inhibits

release of presynaptic excitatory amino acids, de-creases presynaptic calcium conductance and in-creases postsynaptic potassium conductance andthereby maintains afferent neurons in a hyper-polarised state. Baclofen effectively relieves tri-geminal neuralgia, glossopharyngeal neuralgiaand ophthalmic-post-herpetic neuralgia withfewer adverse effects than the alternative, carbam-azepine.[21,148] Baclofen has been successfullycombined with carbamazepine in refractory pain,but with increased risk for drowsiness, nausea andvomiting.

Oral baclofen is rapidly absorbed and has aspecialised transport process necessary for intes-tinal absorption.[148] Peak serum concentrationsoccur within 2 hours, and plasma half-life variesbetween 3 and 7 hours. Baclofen is 80% excretedunchanged in the urine.[148]

Common adverse effects of baclofen are ataxia,dizziness, drowsiness, mental confusion, nauseaand vomiting.[21] Abrupt discontinuation of bac-lofen leads to withdrawal reactions (hallucina-tions, seizures, tachycardia), so the drug should betapered by 5–10mg per day at weekly intervals.[21]

Baclofen cannot be tolerated by 10% of patientsbecause of gastrointestinal upset. Patients with re-nal disease may develop drug toxicity at low dos-ages because of impaired elimination.[148]

The dosage of baclofen is usually 5–10mg twoto three times daily, increased by 5–10mg daily

every 2–3 days as tolerated to a 50–60mg maxi-mum dose per day.

11. Conclusions

The principles of geriatric pain managementcan be summarised by the following points.

1. Use self-assessment tools to measure pain se-verity. Use the same tool consistently on repeatassessment. Unidimensional tools are used for painresponse, multidimensional tools as part of painevaluation.

2. Be aware that pain scales do not avoid theneed for a good pain history and physical exami-nation.

3. Make a reasonably accurate diagnosis to fa-cilitate pain management.

4. Assess the effect of pain on activities of dailyliving and use functional status and daily activitiesas one of the measures of pain relief.

5. Screen for depression, delirium and demen-tia.

6. Use diagnostic procedures for the purpose ofimproving pain management.

7. Treat pain in order to facilitate diagnosticprocedures.

8. Combine pharmacological and non-pharmacological therapies. Use nonpharmacolog-ical therapies that are acceptable to the patient.

9. Mobilise patients physically and psycholog-ically by use of orthopaedic aids, surgery, radiationand other supportive services.

10. Goal orient patients to pain control with im-proved function and use incremental goals such aspain relief that allows for sleep, pain relief at rest,pain control with activities.

11. Start analgesics at a low dose and titrateslowly, particularly in the frail or those with renalor hepatic dysfunction. Table IV provides initialand maximum dosages for analgesics in the el-derly.

12. For opioid administration strategies, takeinto account the severity of the chronic baselinepain and the severity of incident pain. Doses andschedule may need to be independently deter-mined for chronic underlying pain and incident



pain. Dosage needs to be tailored to asymmetricalpain patterns.

13. Use adjuvant analgesics to reduce opioid ad-verse effects and improve pain relief in patientswith poorly controlled pain. Use medicationswhose metabolism is less influenced by age andthat have few adverse effects and drug interactions(table III and table V).

14. The preferred nociceptive adjuvants in theelderly are paracetamol, short-acting NSAIDs,COX-2 inhibitors and sometimes corticosteroids.

15. Rofecoxib is the preferred COX-2 inhibitor.16. Avoid ketorolac, indomethacin, piroxicam

and mefenamic acid.17. Do not combine NSAIDs and corticoste-

roids.18. Combinations of NSAIDs and opioids are

convenient and improve compliance, but are dose-limited by the NSAID.

19. The preferred adjuvant drugs for neuro-pathic pain in the elderly are gabapentin, valproicacid, desipramine and nortriptyline.

Table IV. Equianalgesics in the elderly

Analgesic Initial dosage (oral) Maximum/therapeuticdosagea

Comments

Paracetamol(acetaminophen)

500mg q4h 4000mg Avoid combination with NSAIDs; lower dosage withweight loss, liver disease and regular alcohol use

Naproxen 250mg q8–12h 500mg tid Avoid combining with corticosteroids; do not use inaspirin-sensitive asthma; avoid in renal failure andcongestive heart failure; combine with double-dosehistamine H2 antagonists in high-risk patients; deliriumcan occur when combined with ciprofloxacin

Ibuprofen 200–400mg q4h 800mg tid As for naproxen

Rofecoxib 12.5–25mg od 50mg od Second line; expense may prohibit its use in geriatricpatients (US)

Morphine sulphate 5mg q4h No ceiling ‘Start low, go slow’ in frail elderly; proactively startlaxatives; watch dosage in renal failure

Hydromorphone 1–2mg q4h No ceiling Metabolism similar to morphine; expense may prohibit use

Oxycodone 5mg q4h No ceiling Dosage is less age dependent but very dependent onhepatic and renal function

Methadone 3–5mg q3h as required or3–5mg q8h regularly

No ceiling Requires experience; drug interactions are common(SSRIs, antiepileptic drugs, benzodiazepines); veryinexpensive

Fentanyl 25 µg/h transdermal patchq72h

No ceiling Not versatile; expensive; requires other short-actingsublingual opioids or fentanyl for breakthrough; improvedcompliance

Desipramine 10–25mg qhs 100–150mg Elderly require lower dosages; avoid with cardiacconduction defects; withdrawal reactions if abruptlystopped

Nortriptyline 10–25mg qhs 100–150mg As for desipramine

Methylphenidate 5mg every morning to 5mgbid (morning andafternoon)

10mg bid (morning andafternoon)

Potentiates opioid analgesia; avoid in heart failure anddelirium

Valproic acid 250mg qhs 1000–1500mg od or1000mg bid

Fewer drug interactions than classic antiepileptic drugs;less expensive than gabapentin; rare hepatic toxicity

Gabapentin 100mg q8h 2400–3600mg in divideddoses

Clearance is renal dependent; few drug interactions;withdrawal reactions can occur if stopped abruptly

Dexamethasone 4–8mg bid 100mg Interactions with antiepileptic drugs; taper to lowesteffective dosage

Prednisone 10–20mg bid to tid 60–100mg Same as dexamethasone

a Daily doses unless otherwise indicated.

bid = twice daily; od = once daily; qhs = at night; qxh = every x hours; SSRI = selective serotonin reuptake inhibitor; tid = three times daily.



20. Avoid dextropropoxyphene, pethidine, pen-tazocine and mixed agonist-antagonists and ami-triptyline. Avoid combining classical antiepilepticdrugs with tricyclic antidepressants.

21. Choose opioids based on versatility, poly-pharmacy, severity and type of pain, availability,associated symptoms, and renal and hepatic func-tion.

22. Tramadol and codeine have ceiling dosages,are liable to drug interactions and are greatly influ-enced by hepatic and renal failure; they are notfirst-line analgesics in elderly patients.

23. Morphine is least influenced by hepatic fail-ure but its glucuronide metabolites are greatly af-fected by renal failure.

24. Oxycodone is significantly affected by he-patic and renal failure.

25. Paradoxically, fentanyl accumulates in se-vere renal failure but is relatively safe in hepaticfailure.

26. Methadone requires minor dosage reductionin renal and hepatic failure.

27. Change one drug at a time in patients takingadjuvants and opioids. Simultaneous drug anddose changes lead to confusion, particularly if ad-verse effects occur.

28. Always reassess, particularly if there is achange in pain pattern and severity. Continuity andpersistence are major factors in successful painmanagement.

Acknowledgements

The authors deeply appreciate the expertise of MicheleWells who prepared this manuscript. No sources of fundingwere used to assist in the preparation of this manuscript. Theauthors have no conflicts of interest that are directly relevantto the content of this manuscript.

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