HYDROMORPHONETHERAPEUTICS

Brands� Dilaudid� Exalgo� Palladone (Palladone sales and marketing in U.S.were suspended in 2005 secondary to rapidrelease [dose-dumping] phenomenon whencombined with alcohol) (other names forcontrolled release hydromorphone in othercountries: Hydromorph Contin, Sophidone LP,Jurnista)

� Hydrostat IR

Generic?Yes

Class� Opioids (analgesics)� Hydromorphone is a Schedule III drug under theUS Controlled Substances Act

Commonly Prescribed For(FDA approved in bold)� Management of pain in patients where anopioid analgesic is appropriate, by oral andparenteral route

� Parenteral High Potency (HP) formulation andenteral extended release formulation (Exalgo)are indicated for the relief of moderate-to-severe pain in narcotic-tolerant patients whorequire larger than usual doses of narcoticsto provide adequate pain relief

� The patients who are considered opioid tolerantare those have been taking at least 60 mg of oralmorphine or at least 30 mg of oral oxycodonedaily, or equivalent daily dose of another opioidfor at least a month

� Severe, painful dry coughing� Dyspnea

How the Drug Works� Hydromorphone, a semi-synthetic mu opioidagonist, is a hydrogenated ketone of morphineand shares the pharmacologic properties typicalof opioid analgesics. Opiate receptors arecoupled with G-protein receptors and function asboth positive and negative regulators of synaptictransmission via G-proteins that activate effectorproteins. Binding of the opiate stimulates theexchange of GTP for GDP on the G-proteincomplex. As the effector system is adenylatecyclase and cAMP located at the inner surface

of the plasma membrane, opioids decreaseintracellular cAMP by inhibiting adenylatecyclase. Subsequently, the release ofneurotransmitters such as substance P, GABA,dopamine, acetylcholine, and noradrenaline isinhibited. Opioids also inhibit the release ofvasopressin, somatostatin, insulin and glucagon.Opioids close N-type voltage-operated calciumchannels ([kappa]-receptor agonist) and opencalcium-dependent inwardly rectifyingpotassium channels ([mu] and [delta] receptoragonist). This results in hyperpolarization andreduced neuronal excitability

How Long until It Works� After oral administration of hydromorphone,peak plasma concentrations are generallyattained within 1/2 to 1 hour

� In chronic pain, doses should be administeredaround the clock. A supplemental dose of 5–15%of the total daily usage may be administered every2 hours on an “as-needed” basis

� In patients taking opioid analgesics, the startingdose of hydromorphone hydrochloride shouldbe based on prior opioid usage. Once the totaldaily dosage has been estimated, it should bedivided into the desired number of doses;although only 1/2 to 2/3 of the estimated dosecalculated from equivalence tables should begiven for the first few doses, then increased asneeded according to the patient’s response

� Following extended release (ER) administration,plasma concentrations gradually increase over 6 to8 hours, and thereafter concentrations are sustainedfor approximately 18 to 24 hours post-dose

If It Works� For persistent chronic pain, hydromorphone inextended release formulation can be used forlong term maintenance. In this case, it is alsonecessary to assess the continued need foraround-the-clock opioid therapy periodically

If It Doesn’t Work� Consider switching to another long-acting orextended release opioid preparation

� Consider alternative treatments for chronic pain

Best Augmenting Combosfor Partial Response orTreatment-Resistance

� Short-acting opioids for breakthrough painmight be used

� Add adjuvant analgesics, including calciumchannel alpha-2-delta ligands andantidepressants

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Tests� No specific laboratory tests are indicated

ADVERSE EFFECTS (AEs) AND PATIENTBEHAVIORS DURING THE COURSE

OF OPIOID THERAPY

How Drug Causes AEsVia CNS opioid receptors and opioid receptors inthe periphery� Physical dependencePhysical dependence is defined by the occurrenceof an abstinence syndrome (withdrawal) followingan abrupt reduction of the opioid dose or theadministration of an opioid antagonist. Anabstinence syndrome might include myalgias,abdominal cramps, diarrhea, nausea/vomiting,mydriasis, yawning, insomnia, restlessness,diaphoresis, rhinorrhea, piloerection, and chills.Although there is extensive individual variability, itis prudent to assume that physical dependence willdevelop after an opioid has been administeredrepeatedly for several days. Physical dependenceis not an indicator of addiction. Opioids can besafely discontinued in physically dependentpatients. The syndrome is self-limiting, usuallylasting 3–10 days, and is not life-threatening(unless occurring in highly debilitated patients orpremature infants)� ToleranceTolerance (“true” analgesic tolerance orpharmacodynamic tolerance) describes the needto progressively increase the opioid dose in orderto maintain the same degree of analgesia� Opioid-induced hyperalgesia (OIH)Hyperalgesia is a form of pain hypersensitivity.Hyperalgesia is a symptom of the opioidwithdrawal syndrome seen when opioidadministration is abruptly terminated or reversedby the administration of an opioid antagonist. It isstill debatable if OIH develops independently fromopioid withdrawal or if it becomes moresignificant during withdrawal because itssymptom is no longer opposed by the opioidanalgesic effect. OIH has been observedexperimentally in animals and humans, but itssignificance in clinical settings is still unclear.Based on preclinical studies, opioids are thoughtto have a dual effect: an initial analgesic effectfollowed by the parallel activation of ahyperalgesic system to counteract the analgesiceffect of the opioid. The mechanisms that maycontribute to OIH remain uncertain

� PseudotolerancePseudotolerance is the patient’s perception thatthe drug has lost its effect. It requires a differentialdiagnosis of conditions that mimic “true”analgesic tolerance. These conditions includeprogression or flare-up of the underlying disease,occurrence of a new pathology, increased physicalactivity in the setting of mechanical pain, lack oftreatment adherence, pharmacokinetic tolerance,manufacturing differences of the same opioidagent, and OIH� AddictionA primary, chronic, neurobiologic disease, withgenetic, psychosocial, and environmental factorsinfluencing its development and manifestations. Itis characterized by behaviors that include one ormore of the following: impaired control over druguse, craving, compulsive use, and continued usedespite harm� Aberrant behaviorsOpioids are the second most commonly abuseddrugs in this country. Aberrant behaviors include awide variety of actions, some of criminal purpose:� selling prescription drugs� prescription forgery� stealing another patient’s drugs� injecting oral formulations� obtaining prescription drugs from nonmedicalsources

� concurrent use of licit or illicit drugs� multiple unauthorized and uncontrollable doseescalations

� PseudoaddictionPseudoaddiction refers to the occurrence ofproblematic behaviors related to extreme anxietyassociated with unrelieved pain. This includesunsanctioned dose escalation, aggressivecomplaining about needing more drugs, andimpulsive use of opioids. It can be differentiatedfrom addiction by the disappearance of thesebehaviors when access to analgesic medications isincreased and pain control is improved� Opioid-induced constipation (OIC)Opioid-induced constipation is a common AEassociated with opioid therapy. OIC is commonlydescribed as constipation; however, it refers to aconstellation of adverse GI effects, which alsoincludes abdominal cramping, bloating,gastroesophageal reflux disease (GERD), andgastroparesis. The mechanism for these effects ismediated primarily by stimulation of opioidreceptors in the GI tract. In patients with pain,uncontrolled symptoms of OIC can add to theirdiscomfort and may serve as a barrier to effectivepain management by limiting therapy or prompting

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discontinuation. Prophylactic treatment should beprovided for constipation. Constipation can bemanaged with peripherally acting opioidantagonist compounds (e.g. alvimopan,methylnaltrexone) when available or by a stepwiseapproach that includes an increase in fluids andosmotic agents (e.g. sorbitol, lactulose), or witha combination stool softener and a mildperistaltic stimulant laxative such as senna orbisacodyl, as needed. Oral naloxone, which hasminimal systemic absorption, has also been usedempirically to treat constipation without reversinganalgesia in most cases� Nausea and vomitingA meta-analysis of opioids in moderate tosevere noncancer pain found nausea toaffect 21% of patients. Opioids can causedizziness, nausea, and vomiting by stimulating themedullary chemoreceptor trigger zone, increasingthe inner ear vestibular system (i.e., motionsickness), or inducing gastroparesis (or evenGERD).With vomiting, parenteral administration

of antiemetics may be required. If nausea iscaused by gastric stasis, treatment is similar tothat of GERD. Tolerance to nausea usuallydevelops� Biliary tract increased pressures and/orspasm

� DrowsinessCommon, related to dose, especially observed atinitiation of treatment or when dose is increased.Tolerance may develop over time.Daytime drowsiness can be minimized by

using a low starting dose and titratingprogressively. If somnolence does occur, itusually subsides within a few days as tolerancedevelops. The use of a stimulant (e.g. modafinil,methylphenidate) can be considered if persistentsomnolence has a detrimental effect on thepatient’s functioning� DeliriumDelirium is frequent in elderly patients, particularlythose with cognitive impairment. It can beprevented or treated by using low doses ofIR opioids and discontinuing other CNS-actingdrugs� HypogonadismHypogonadism (low testosterone serum levels)can occur in male patients. The testosterone levelshould be verified in patients who complain ofsexual dysfunction or other symptoms ofhypogonadism (e.g. fatigue, anxiety, depression).Testosterone supplementation may be effective intreating hypogonadism, but close monitoring of

the testosterone serum level as well as screeningfor benign prostate hypertrophy and prostatecancer should be carried out

Life-Threatening orDangerous AEs

� In overdose or when taken with CNSdepressants, respiratory depression

� However, though respiratory depression fostersthe greatest concern, tolerance to this AEdevelops rapidly. Respiratory depression is veryuncommon if the opioid is titrated according toaccepted dosing guidelines

Weight Gain� Unusual

commonunusual not unusual problematic

Sedation� Common

common problematicunusual not unusual

� Many experience and/or can be significantin amount

� Dose-related: can be problematic at high doses� Can wear off with time but may not wear off athigh doses

What to Do about AEs� Wait while treat AE symptomatically� Lower the dose� Switch to another opioid agent� The assessment and management of AEs is anessential part of opioid therapy. By adequatelytreating AEs, it is often possible to titrate theopioid to a higher dose and thereby increase theresponsiveness of the pain

Because different opioids can produce differentadverse effects in a given patient, opioid rotation isan option for the treatment of persistent AEs

DOSING AND USE

Usual Dosage Range� Opioid-naïve patients:� OR: 2–4 mg every 4–6 hours. A gradualincrease in dose may be required if analgesia isinadequate, as tolerance develops, or if pain

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severity increases. The first sign of tolerance isusually a reduced duration of effect

� SC/IM: 0.4–1.2 mg every 2–3 hours, asnecessary

� IV: 0.2–1 mg every 2–3 hours� Conversion from prior opioid:� OR: Patients receiving oral immediate-releasehydromorphone: starting dose equivalent (ER) tothe patient’s total daily oral hydromorphonedose, taken once daily. Patients receiving anotheroral opioid: start ER therapy by administering50% of the calculated total daily dose every24 hours. The initial dose of hydromorphone ERcan be titrated until adequate pain relief withtolerable AEs have been achieved

� Parenteral: Convert the current total dailyamount(s) of opioid(s) received to an equivalenttotal daily dose of hydromorphone and reduceby one-half due to the possibility of incompletecross-tolerance. Divide the new total amount bythe number of doses permitted based on dosinginterval (e.g. 8 doses for every 3-hour dosing).Titrate the dose according to the patient’sresponse. Do not use hydromorphone-HP forpatients who are not tolerant to the respiratorydepressant or sedating effects of opioids

Dosage Forms� Oral liquid (HCl): 1 mg/mL� Immediate release tablet: 2, 4, and 8 mg� Extended release tablet: 8, 12, and 16 mg� Injection: 1, 2, and 4 mg/mL; HP: 10 mg/mL

How to Dose� Initiate the dosing regimen for each patientindividually, taking into account the patient’sprior analgesic treatment

� Use hydromorphone-HP only for patients whorequire the higher concentration and lower totalvolume of the ampoule

� Titrate patients to adequate analgesia with doseincreases not more often than every 3–4 daysand not higher than 25–50% of the current dailydose, in order to attain steady-state plasmaconcentrations of hydromorphone at each dose

� If more than 2 doses of rescue medication areneeded within a 24-hour period for 2consecutive days, the dose may need to betitrated upward

� The ER formulation is to be administered nomore frequently than every 24 hours

Dosing Tips� Oral dosages higher than the usual dosages maybe required in some patients

� The dosage of opioid analgesics likehydromorphone hydrochloride should beindividualized for any given patient, sinceadverse events can occur at doses that may notprovide complete freedom from pain

� If pain management is not satisfactory and in theabsence of significant opioid-induced adverseevents, the hydromorphone dose may be increasedgradually. If excessive opioid AEs are observed earlyin the dosing interval, the hydromorphone doseshould be reduced. If this results in breakthroughpain at the end of the dosing interval, the dosinginterval may need to be shortened. Dose titrationshould be guided more by the need for analgesiathan the absolute dose of opioid employed

� ER hydromorphone must be taken once everyday, at around the same time each day. Theformulation should be swallowed whole – nevercrushed or chewed

� If a patient needs more than 2–3 extra doses ofshort acting hydromorphone in a day, the doseof ER hydromorphone may need to be reviewed

Overdose� Confusion, extreme sedation, respiratorydepression, and death

� Fatalities have been reported due to overdose bothin monotherapy and in conjunction with sedatives,in particular benzodiazepines, or alcohol use

Long-Term Use� The patients will develop physical dependenceand may develop tolerance on long-term use

� In patients with addiction vulnerability, risk ofaberrant behaviors and addiction

How to Stop� When the patient no longer requires therapy withhydromorphone, taper doses gradually, by25–50% every 2 or 3 days down to the lowestdose before discontinuation of therapy, toprevent signs and symptoms of withdrawal inthe physically dependent patient

Pharmacokinetics� Hydromorphone is extensively metabolized viaglucuronidation in the liver, with greater than95% of the dose metabolized tohydromorphone-3-glucuronide along with minoramounts of 6-hydroxy reduction metabolites

Drug Interactions� The concomitant use of other CNS depressantsincluding sedatives or hypnotics, generalanesthetics, phenothiazines, tranquilizers, and

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alcohol may produce additive depressant effects.Respiratory depression, hypotension, and profoundsedation or coma may occur. When such combinedtherapy is contemplated, the dose of one or bothagents should be reduced. Narcotic analgesics,including hydromorphone, may enhance the actionof neuromuscular blocking agents and produce anincreased degree of respiratory depression

Other Warnings/Precautions

� Safety and effectiveness in children have notbeen established

� Respiratory depression is the chief hazard ofhydromorphone. Respiratory depression is morelikely to occur in the elderly, in the debilitated,and in those suffering from conditionsaccompanied by hypoxia or hypercapnia wheneven moderate therapeutic doses maydangerously decrease pulmonary ventilation

� Hydromorphone may be expected to have additiveeffects when used in conjunction with alcohol, otheropioids, or illicit drugs that cause CNS depression

� Infants born to mothers physically dependent onhydromorphone will also be physicallydependent and may exhibit respiratorydifficulties and withdrawal symptoms

� The respiratory depressant effects ofhydromorphone with carbon dioxide retention andsecondary elevation of cerebrospinal fluid pressuremay be markedly exaggerated in the presence ofhead injury, other intracranial lesions, orpreexisting increase in intracranial pressure

� Opioid analgesics, including hydromorphone,may cause severe hypotension in an individualwhose ability to maintain blood pressure hasalready been compromised by a depleted bloodvolume, or a concurrent administration of drugssuch as phenothiazines or general anesthetics

� Hydromorphone should be given with caution andthe initial dose should be reduced in the elderly ordebilitated and those with severe impairment ofhepatic, pulmonary or renal functions; myxedema orhypothyroidism; adrenocrotical insufficiency(e.g. Addison’s disease); CNS depression or coma;toxic psychoses; prostatic hypertrophy or urethralstricture; gall bladder disease; acute alcoholism;delirium tremens; kyphoscoliosis; or followingGI surgery. The administration of opioid analgesicsincluding hydromorphone may obscure thediagnoses or clinical course in patients with acuteabdominal conditions andmay aggravate preexistingconvulsions in patients with convulsive disorders

� Hydromorphone may impair mental and/orphysical ability required for the performance of

potentially hazardous tasks (e.g. driving,operating machinery)

� Opioid analgesics, including hydromorphonehydrochloride tablets, should also be used withcaution in patients about to undergo surgery ofthe biliary tract since they may cause spasm ofthe sphincter of Oddi

� ER formulation does not prevent patients fromdeveloping opioid dependence

SPECIAL POPULATIONS

Hepatic or Renal Impairment� After oral administration of hydromorphone,exposure to hydromorphone (Cmax and AUC 0–48)is increased in patients with impaired renal/hepaticfunction by 2- to 4-fold in moderate (CLcr¼40–60 mL/min; Child–Pugh Group B) and 3-fold insevere (CLcr<30 mL/min) renal impairment(pharmacokinetics of hydromorphone in severehepatic impairment patients has not been studied)compared with normal subjects (CLcr>80 mL/min). In addition, in patients with severe renalimpairment hydromorphone appeared to be moreslowly eliminated with longer terminal eliminationhalf-life (40 hours) compared to patients withnormal renal function (15 hours). Patients withmoderate renal/hepatic impairment should bestarted on a lower dose. Starting doses forpatients with severe renal/hepatic impairmentshould be even lower. Patients with renal/hepaticimpairment should be closely monitored duringdose titration. Use of oral liquid is recommended toadjust the dose

Elderly� Age has no effect on the pharmacokineticsof hydromorphone

Children and Adolescents� Safety and effectiveness in children have notbeen established

Pregnancy� Category C� No adequate and well-controlled studies inpregnant women

� Hydromorphone crosses the placenta. Maycause respiratory compromise in newbornswhen administered during labor and delivery

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Breast-Feeding� Hydromorphone is found in low levels in breastmilk

� Withdrawal symptoms can occur inbreast-feeding infants when maternaladministration of an opioid analgesic is stopped

� Hydromorphone is not recommended for use innursing women

THE ART OF PAIN PHARMACOLOGY

Potential Advantages� Potent analgesia� Less itching and nausea than morphine

Potential Disadvantages� Metabolites, although thought to be lessproblematic than those of morphine, may be anissue if using high doses in patients with renalfailure (hydromorphone-3-glucuronide)

Primary Target Symptoms� Acute or chronic pain

Pearls� 4 to 5 times more potent than morphine� It causes less nausea and pruritus than morphine� Although evidence is still limited, it seems saferin renal failure than morphine

Universal Precautions and RiskManagement Plan� Opioids are highly effective drugs for treatingmoderate to severe pain. However, both patients’and physicians’ fears of drug abuse and addiction(and potential associated legal sanctions) are animportant barrier to the effective use of opioids forthis indication. Unfortunately, this can result in theundertreatment of pain.

� The physician is responsible for assessingwhether the patient is at a relatively low or highrisk of addiction and/or abuse. Risk factors foraddiction can be divided into three categories:� Genetic factors (e.g. family history ofaddiction). One of the most consistentpredictors of addiction is a personal or familyhistory of substance abuse

� Psychosocial factors (e.g. depression, anxiety,personality disorder, childhood abuse,unemployment, poverty)

� Drug-related factors (e.g. neuroadaptationassociated with craving)

� The application of a standardized approach tomanaging chronic pain patients with opioids hasbeen referred to as UNIVERSAL PRECAUTIONS.An integral component of such precautions isthe implementation of a risk management plan,including strategies to monitor, detect, manage,and report addiction or abuse. The followingpoints are of relevance:1. Interview and examine the patient2. Try to establish the pain diagnosis, outline

the differential diagnosis3. Recommend the appropriate diagnostic

work-up4. Discuss opioid therapy, benefits and risks,

and potential exit strategies. The criteria forstopping opioid therapy should be discussedwith the patient prior to starting therapy, anda written exit strategy should be in place, incase the patient:✓ fails to show decreased pain or increased

function with opioid therapy✓ experiences unacceptable AEs or toxicity✓ violates the opioid treatment agreement

(see below)✓ displays aberrant drug-related behaviors

5. Perform a psychosocial assessment of thepatient including screening for low or high riskof addictive disorders; proactive screeningstrategies should be employed, based on theperceived level of risk. Validated screening toolsand questionnaires for patients with paininclude: (1) opioid risk tool (ORT) www.painknowledge.org/physiciantools/ORT/ORT%20Patient%20Form.pdf, (2) screener and opioidassessment for patients with pain (SOAPP)www.painedu.org/soapp-development.asp. Ifappropriate, obtain urine drug testing (UDT) atbaseline

6. Document informed consent and treatmentagreement

7. Initiate trial of opioid therapy � adjuvantmedications

8. Assess ANALGESIA, ACTIVITY, ADVERSEEFFECTS, and ABERRANT BEHAVIORS (4As)at follow-ups. For assessments of painand function may use the Brief PainInventory (BPI). Pill count and urine drugtesting are the most common strategies toassess compliance. UDT can be performed tocheck for the presence of prescribedmedications as evidence of their use, and forthe presence of illicit drugs. A negative testfor prescribed medications does notnecessarily indicate diversion, but could bedue to laboratory test inaccuracy or to

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inadequate dosing or problematic use. Thisresult would, however, merit furtherdiscussion with the patient. The aim of UDTis not simply to ensure adherence, but toenhance the doctor–patient relationship byproviding documentation of adherence to thetreatment plan. If problematic or aberrantbehavior is identified, the physician shouldreassess the patient to provide a potentialdiagnosis (e.g. pseudoaddiction,psudotolerance, cognitive impairment,encephalopathy, anxiety or personalitydisorder, depression, addiction, criminalactivity)

9. Continue or discontinue opioid therapy, ordischarge patient from practice. On the basisof the severity of the problematic behavior,patient history, and the findings of thereassessment, the physician must make adecision regarding treatment continuationand referral (e.g. to an addiction specialist).Treatment should only be continued if painrelief and maintained function are evident,control over the therapy can be reacquired,and there is improved monitoring. Anychanges in the treatment plan must becomprehensively documented. All physiciansshould follow federal and state lawsregarding the prescribing of controlledsubstances. Regarding the prescription ofopioids to a reliable and clinically stablepatient who is affected by a chronic disablingpainful disorder, federal regulations arearticulated under the Controlled SubstancesAct (CSA) and monitored by the DrugEnforcement Administration (DEA)

10. Avoid withdrawal symptoms if youdiscontinue opioid therapy by using aslow tapering schedule (reducing theopioid dose by 10–20% each day).Anxiety, tachycardia, sweating, and otherautonomic symptoms that persist may belessened by slowing the taper. Clonidine at adose of 0.1–0.3 mg/day over 2–3 weeks canbe recommended for individuals who areknown to have a history of a problematicwithdrawal

Opioid Treatment Agreement� Before the start of therapy, the expectations andobligations of both the patient and physicianshould be clearly established in a written orverbal agreement. The opioid agreementfacilitates informed consent, patient education,and adherence to the treatment plan

� As a tool, the opioid agreement may also describethe treatment plan for managing pain, provideinformation about the AEs and risks of opioids,and establish boundaries and consequences foropioid misuse or diversion. The agreement canhelp to reinforce the point that opioid medicationsmust be used responsibly, and assure patientsthat these will be prescribed as long as theyadhere to the agreed plan of care. An exampleof an agreement is available for perusal atwww.ampainsoc.org/societies/mps/downloads/opioid_medication_agreement.pdf

Patient Education� Patient education is an essential part of opioidtherapy; it should begin before therapy isinstituted, and continue throughout the course oftreatment. The physician has to address thefollowing components of education while talkingto the patient:� Opioids are powerful pain-relieving drugs, andare effective in a number of painful disorders.However, they are strictly regulated and mustbe used as directed, and only by the patient forwhom they are prescribed

� The goals of pain management are to help thepatient feel better and live a more active life. Ittakes more than pain medications: wellnessprogram, comprehensive assessment,exercises, appropriate diet, physical therapy,and relaxation are also very important

� Thesemedicines cannot be stopped abruptly, andthey need to be tapered off gradually and onlyunder and according to the physician’s directions

� Common AEs include nausea, dry mouth, anddrowsiness with cognitive impairment,impaired voiding, and itchy skin. These usuallylast 1–2 weeks until tolerance develops. Theycan be managed. Nausea and itch may beprevented by antiemetics. Constipation doesnot go away, but can usually be managed byeating the right foods, drinking enough liquids,and, as a rule, always taking some laxatives

� The patient has to work with his/her painmanagement team

� A patient information sheet can be downloadedfrom www.ohsu.edu/ahec/pain/patientinformation.pdf.

Goals of Opioid Therapy� The goal of opioid therapy is to provide analgesiaand to maintain or improve function, withminimal AEs. The careful use of opioidanalgesics may be considered in the treatment ofpain when nonopioid analgesics (e.g.acetaminophen, NSAIDs, calcium channel

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alpha-2-delta ligands, duloxetine) andnonpharmacologic options have proveninadequate for pain control. When medicallyappropriate, opioid analgesics can berecommended for chronic, moderate to severepain, which, for practical purposes, is defined aspain of intensity >4 on the numerical ratingscale 0–10 (where 0 means no pain and 10 theworst pain imaginable)

� Opioids are still considered among the mostpotent and effective “broad-spectrum”

analgesics in the treatment of acute and chronicpain. As such, they have been prescribed topatients suffering from moderate to severedisabling pain of both cancer and noncancerorigin. The indications for the use of opioids inmoderate to severe chronic pain of noncancerorigin are osteoarthritis, musculoskeletal pain,and neuropathic pain, with the commondenominator that various pharmacologic andnonpharmacologic procedures have provedunsuccessful

� It is crucial to recognize that patients will responddifferently to various opioids in terms of bothpotency and effectiveness. Variability amongpatients can be quite profound. This can extendtowards both the analgesic effects and the AEs.Reports of lack of analgesic effects should bechecked for regimen and adherence. Predicting apatient’s response to medication has long been agoal of clinicians; it is possible thatpharmacogenomics may, in due course, becomein common use for screening for variations in theexpression of drug-metabolizing enzymes (e.g.cytochrome CYP3A4), and thus provide a potenttool for improving pain management

Opioid Rotation� Opioid rotation refers to the switch fromone opioidto another, and it can be recommended when AEsor onset of analgesic tolerance limit the degree ofanalgesia obtained with the current opioid; opioidrotation is commonly recommended andperformed between pure opioid agonists. In painmanagement, opioid rotation of mixed opioidagonist–antagonists to/from pure opioid agonistscan be difficult and clinically unfeasible to becarried out. If necessary, it is recommended thatthe initial opioid (e.g. a pure agonist) be tapereddown and almost discontinued before startingwiththe upward titration of the new opioid

� According to clinical experience andobservations, opioid rotation may result inclinical improvement in >50% of patients with

chronic pain who have had a poor response toone opioid

� Opioid rotation should always be based on anequianalgesic opioid conversion table, whichprovides values for the relative potencies amongdifferent opioid drugs. The first step is todetermine the patient’s current total daily opioidutilization. This can be accomplished by addingup the doses of all long-acting and short-actingopioids taken by the patient per day. If thepatient is on multiple opioids, convert all of themto morphine equivalents using standardequianalgesic tables

� Usually, when switching from opioid A to opioidB, it is initially prudent to reduce the calculatedequianalgesic dose of opioid B by 50%. If opioidB is methadone, and you are switching from�200 mg/day dose of morphine or morphineequivalent, the initially calculated dose ofmethadone should be reduced by 90%, andgiven in divided doses not more often than every8 hours. If you are rotating to opioid B andopioid B is transdermal fentanyl, then maintainthe equianalgesic dose

� The initial dose of opioid B should also be furtherreduced based on clinical circumstances, forexample in the elderly or in patients who havesignificant cardiopulmonary, hepatic, or renaldisease

� The patient must remain under close clinicalsupervision to prevent overdose. Undersupervision, a safe, effective, and rapid opioidrotation and titration (RORT) can also beperformed via IV patient-controlled analgesia. Thisoption should be considered for patients withsevere disabling pain who are on large daily dosesof opioids, including oral methadone or multipleopioids, and for frail or elderly patients

Intrathecal Analgesic Therapies

OtherCombo/Agents

Sufentanil(S)

S+ B/C+ Z

C M/HM/F+ B/C+ Z

Fentanyl(F)

M/HM+ Z

Morphine(M)

Hydromorphone(HM)

Ziconotide(Z)

4th Line

3rd Line

2ndLine

1stLine

Smith HS, et al. Pain Physician. 2008, 11:S89-S104.

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Suggested ReadingAmerican Pain Society. Principles of AnalgesicUse in the Treatment of Acute Pain and CancerPain, 5th edn. Glenview, IL: American PainSociety, 2003.

Fine PG, Portenoy RK. A Clinical Guide toOpioid Analgesia. Minneapolis, MN: McGraw-Hill,2004.

Fudin J, Smith HS, Toledo-Binette CS, Kenney E,Yu AB, Boutin R. Use of continuous ambulatoryinfusions of concentrated subsutaneous (s.q.)hydromorphone versus intravenous (i.v.) morphine:cost implications for palliative care. Am J Hosp PalliatCare 2000;17(5):347–53.

Gallagher R. Opioids in chronic pain management:navigating the clinical and regulatory challenges.J Family Pract 2004;53(Suppl.):S23–32.

Gourlay DL, Heit HA. Universal Precautions revisited:managing the inherited pain patient. Pain Med 2009Jul;10(Suppl 2):S115–23.

Heit HA. Addiction, physical dependence, andtolerance: precise definitions to help cliniciansevaluate and treat chronic pain patients. J Pain PalliatCare Pharmacother 2003;17:15–29.

Heit HA, Gourlay DL. Urine drug testing in painmedicine. J Pain Symptom Manage 2004;27:260–7.

Korkmazsky M, Ghandehari J, Sanchez A, Lin HM,Pappagallo M. Feasibility study of rapid opioid rotationand titration. Pain Physician 2011;14(1):71–82.

Pappagallo M. Incidence, prevalence, andmanagement of opioid bowel dysfunction. Am J Surg2001;182(5A Suppl):11S–18S.

Raja S, Haythornthwaite J, Pappagallo M, et al.Opioids versus antidepressants in postherpeticneuralgia: a randomized-placebo controlled trial.Neurology 2002;59:1015–21.

Smith HS. The metabolism of opioid agents and theclinical impact of their active metabolites. Clin J Pain2011;27(9):824–38.

Smith HS. Opioid metabolism. Mayo Clin Proc 2009;84(7):613–24.

Smith HS. Opioid Therapy in the 21st Century.Oxford, UK: Oxford University Press, 2008.

Swegle JM, Logemann C. Management of commonopioid-induced adverse effects. Am Family Phys2006;74:1347–54.

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