Pharmacological Management of

Severe Pain

Donato G. Dumlao, MD, FACP

SMC Palliative Care ServicesHouston, Texas

Tammy L. Groher, NPPalliative Care Nurse Practitioner,

Saint Joseph’s Hospital, Atlanta

“The alleviation of suffering is universally acknowledged as a cardinal goal of medical

care”

Doyle et al

Goals of Palliative Medicine

• Improve or maintain the quality of life

• Alleviate suffering• Maintain functionality, if

possible• Near the end of life, functionality

can be sacrificed as long as suffering is alleviated

Significance of Severe Pain

“Worse than torture”

Torture InstrumentsTorture Instruments

Cancer PainCancer Pain

• Most common reason to Most common reason to seek medical attentionseek medical attention

• 60-90% with advance 60-90% with advance cancer have paincancer have pain

• 50 to 75%% report 50 to 75%% report inadequately relievedinadequately relieved painpain

• 25 % die with unrelieved 25 % die with unrelieved excruciating painexcruciating pain

• 80-90% can be 80-90% can be managed relatively managed relatively simple with oral simple with oral analgesicsanalgesics

• ECOG Study of 15 ECOG Study of 15 Cancer CentersCancer Centers– 61% percent of the 61% percent of the

sample had pain sample had pain – 40% of those with pain 40% of those with pain

rated it as significant rated it as significant (i.e., greater than 5 on (i.e., greater than 5 on a 0 to 10 scale)a 0 to 10 scale)

– No patient in this No patient in this sample was reported to sample was reported to be receiving morphine be receiving morphine or a morphine-like or a morphine-like opioid opioid

HIV/AIDS Pain Syndromes

• 25 % in asymptomatic phase• 40-50 % of ambulatory patients with

AIDS• 80 % hospitalized patients with advance

disease• Pain in HIV/AIDS is dramatically under

treated• Only 6% of AIDS patient with severe

pain are on opioid analgesics (Oxford Textbook of Palliative Medicine)

Pain Among Those With Neurological Disorders

• CVA– Loss of muscular ensheathment to bones and joint, contractures,

frozen joints– Skin pressure pain– 18 to 32 % post-stroke headache– 20 to 30% hand shoulder syndrome

• MS– 50 to 60 % have several pain syndromes – Trigeminal neuralgia, Lhermitte’s sign, central dysaesthetic

pain, headache, optic neuritis, and painful tonic spasm• Parkinson’s:

– Stiffness, rigidity causes dystonic spasms• Spinal cord injuries:

– About one-quarter to one-third of patients have severe chronic pain that significantly affects quality of life

The undertreatment of pain is still a major issue

in both oncology and palliative medicine

Indifference to Pain

Only a few healthcare professionals will ever experience

and understand chronic excruciating pain

D. Dumlao

Barriers to Effective Pain Management

• Not recognizing the importance of pain• Prejudices about pain • Fears of abuse and addiction• Unpleasant experiences with pain

therapy (intolerable side effects: nausea, drowsiness, fatigue, constipation)

• Regulatory restrictions • Insufficient knowledge of

pharmacological therapy

Addiction vs. Addiction vs. PseudoaddictionPseudoaddiction

Addiction• Chronic

neurobiological disorder

• Genetic, psychological and social components

• Characterized by impaired ability to control drug use and continue use despite recurrent problems related to self administration

Pseudoaddiction• Arises when pain is

inadequately managed• May result from prn

dosing schedules with inadequate potency and/or frequency

• Staff responds by using this as evidence of drug addiction

• Adequate pain control resolves aberrant behavior and improves function

Risk of Addiction and Substance Use Disorders

among Patients Receiving Opioid Medications

• Actual risk is low• The risk is over estimated• Physical dependence is not addiction• These concerns results in physician

reluctance to write opioids and patient reluctance to use them

Barriers involving healthcare systems have been reduced since

the standards of the JCAHO---Which asserts that pain management is

a patient right

However, barriers, such as failure to adhere to

standards and guidelines, still exist

“The doctor who leaves a patient to suffer intolerably is more morally reprehensible than the doctor who opts for

death assistance”

Robert Twycross

Pharmacological Therapy: Pharmacological Therapy: Opioid AnalgesicsOpioid Analgesics

• Major class of drugs used in pain Major class of drugs used in pain managementmanagement

• There is considerable inter-There is considerable inter-individual variability in response individual variability in response to each opioidto each opioid

• Agonists have no relevant ceiling Agonists have no relevant ceiling effect to analgesiaeffect to analgesia

• Adverse effect limits useful doseAdverse effect limits useful dose

Goal of Pain ManagementGoal of Pain Management

Titrate dose until Titrate dose until adequate pain control is adequate pain control is achieved or intolerable achieved or intolerable adverse or toxic effects adverse or toxic effects

manifestmanifest

Pharmacokinetics of Pharmacokinetics of OpioidsOpioids

• Renal Excretion Renal Excretion • Metabolized in the liverMetabolized in the liver• Concern is with toxic metabolites which can cause Concern is with toxic metabolites which can cause

neurotoxicityneurotoxicity– 6 morphine glucuronide6 morphine glucuronide– NormeperdineNormeperdine– NorpropoxypheneNorpropoxyphene– 6 hydromorphone6 hydromorphone– NorfentanylNorfentanyl

• Onset of action ranges from 0 to 15 minutes (IV) Onset of action ranges from 0 to 15 minutes (IV) or 15 to 30 minutes (po) (depends on lipid or 15 to 30 minutes (po) (depends on lipid solubility)solubility)

• Duration of actionDuration of action

Pharmacokinetics of Pharmacokinetics of Commonly Used OpioidsCommonly Used Opioids

• Dilaudid: Dilaudid: – Half life: 1 to 3 hoursHalf life: 1 to 3 hours

• Morphine: Morphine: – Duration of analgesia: 2 to 6 hoursDuration of analgesia: 2 to 6 hours– Half life: 2 to 4 hoursHalf life: 2 to 4 hours

•   Fentanyl: Fentanyl: – Duration of analgesia: 0.5 – 1 hourDuration of analgesia: 0.5 – 1 hour– I.V half life: 2 - 4 hoursI.V half life: 2 - 4 hours– Transdermal patch half life: 17 hours (13-22 hours, half-life is Transdermal patch half life: 17 hours (13-22 hours, half-life is

influenced by absorption rate)influenced by absorption rate)– Transmucosal half life: Lozenge: 7 hoursTransmucosal half life: Lozenge: 7 hours– Buccal film: 14 hours Buccal film: 14 hours – Buccal tablet half life: 100-200 mcg: 3-4 hours, 400-800 mcg: 11-12 Buccal tablet half life: 100-200 mcg: 3-4 hours, 400-800 mcg: 11-12

hourshours • Methadone Methadone

– Duration of analgesia: Oral: 4-8 hours, increases to 22-48 hours with repeated Duration of analgesia: Oral: 4-8 hours, increases to 22-48 hours with repeated dosesdoses

– Half-life elimination: 8-150 hoursHalf-life elimination: 8-150 hours

What Opioid Analgesic to Use?

• Pharmacokinetics• Patient co-morbidities ( Kidney and liver

Disease: Methadone or Fentanyl)• Intensity of pain• Previous experience with opioid analgesics

– Considerable inter-individual variability in response to each opioid

– Adverse events– True allergy to opioids (Drugs of choice: Methadone or

Fentanyl)

• Etiology of pain– Nociceptive– Neuropathic– Opioid Induced Hyperalgesia

• Total daily dose of pain medications

When To Start IV Opioid Analgesics

• Loss of gut function• Sublingual morphine will not

control breakthrough pain of patients on mega doses

• Requires rapid onset of analgesia• Requires very high doses• Cost

Determine the dose that will control

excruciating pain

The best pain medication is the drug that will control

pain without adverse effects

What Dose to Give an Opioid Naïve Patient?

• For opioid naïve start at a morphine equivalent of 2 to 5 mg IV or 10 mg PO

• Dose escalation should be more than 30 to 50% of base dose to observe a meaningful change.

• Frequency of parenteral dosing can be as often as every 15 to 30 minutes until adequate analgesia is achieved

Opiod Analgesic Usual Opiod Analgesic Usual Starting DoseStarting Dose

Drug Equianalgesic parenteral dose

Starting iv dose

iv:po ratio Starting dose po /transdermal

Duration of Action

Morphine 10 mg Bolus dose=0.05-0.1 mg q 2-4 hours

Continuous infusion=0.01-0.04 mg/kg/hr

1:3 0.15-0.3 mg/kg/dose q 4 hours

3-4 hours

Hydromorphone 1.5 mg 0.015-0.02 mg/kg q 4

1:5 0.06 mg/kg q 3 to 4 hours

2-4 hours

Oxycodone 5-10 mg N/A 0.1-0.2 mg/kg q 3 to 4

3-4 hours

Fentanyl 100mcg 1 to 2 mcg/kg/hr as continuous infusion

25 mcg patch 72 hours

Methadone 10 mg 0.1 mg/kg q 4 to 8 hours

1:2 0.2 mg/kgq 4 to 8 hours

12 to 150 hours

Once Analgesia is Achieved

• A regular dosing schedule of every four hours can be started

• Rescue or breakthrough dosing– 30% to 50% of every 4 hour dosing– 10 to 15 percent of total 24 hour dose– Best time to give rescue dose is time of

peak onset

• Convert to PO or transdermal if possible

The Opioid Tolerant Patient

• Etiology of pain– Nociceptive– Neuropathic– Opioid Induced Hyperalgesia

• Has there been progression of pain due to progression of disease or some other factors

• Some cases might require opioid rotation not a dose increase

• Previous response to opioids.

Dosing an Opioid Tolerant Patient

• Always continue or convert chronic stable dose of home opioid analgesic. Be creative. May combine po with iv or transdermal with iv

• There is incomplete cross tolerance among opioids. Because of this when converting stable doses use 75% of conversion dose if pain is fairly controlled

• If pain is uncontrolled you may use 100% of conversion dose

• Be sure breakthrough or rescue regimen is ordered

Conversion TableConversion TableMorphine PO

3 1

Dilaudid IV 1 5

1 20

Dilaudid PO 1 2

1 8

5 1

Methadone PO

1 2

1 6

2 1

Oxycodone PO

1.5 1

1 2

10 1

4 1

33

11

Morphine IV Morphine PO

Dilaudid IV Dilaudid PO Methadone PO

10 mcg IV Fentanyl =1 mg IV morphine

25 mcg TD Fentanyl/HR = 45 mg PO Morphine

IV Fentanyl 1:4 TD Fentanyl

200 mcg Actiq = 10 mg oxycodone

Morphine to Methadone ratio30 to 90 mg morphine = 4:191 to 300 mg = 8:1>300 mg =12:1

1mg IV methadone = 2 mg PO methadone

Advantages of Patient Advantages of Patient Controlled AnalgesiaControlled Analgesia

• Circumvents Circumvents repetitive injectionsrepetitive injections

• Prevents delays in Prevents delays in analgesic analgesic administrationadministration

• Provides continuous Provides continuous level of pain controllevel of pain control

• Decreased side Decreased side effectseffects

• Less breakthrough Less breakthrough painspains

• Prompt deliveryPrompt delivery

• Patients administer Patients administer analgesic based on analgesic based on pain levelpain level

• EconomicalEconomical• Not nurse Not nurse

dependentdependent• Lower Overall Lower Overall

narcotic usenarcotic use• High degree of High degree of

safetysafety

Disadvantages of Basal Dosing with PCA

• May increase adverse effects like – Sedation– Nausea – Respiratory depression

Dosing Consideration for PCA

• Basal dose depends on chronic stable home dose.

• Demand dose can range from 25 to 200% of hourly basal or background dose. As to interval or lockout, q 5 to q 15 minutes is acceptable.

• Upward titration is dependent on dose patient can tolerate. Check hourly delivered doses and 24 hour total doses.

• Monitor number of attempts and correlate to the number of doses delivered

Upward Titration of Basal PCA Dose

• Increase by at least 25 to 50% of hourly dose

• Increase by getting hourly average of demand doses during a given time period and adding the average to the hourly basal dose

• Increase basal dose by adding 1 demand dose to the basal dose

• Monitor closely during the first 3 to 4 hours of initiating a new dose. It is important to note if patient can tolerate the dose

Three Complications of Chronic High Dose Opioid

Therapy•Neurotoxicity•Tolerance •Opioid Induced Hyperalgesia

Opioid-induced Neurotoxicityity

• Mediated through non-opioidergic mechanisms

• Due to neuro-excitatory metabolites of opioids (morphine-6-glucuronide, oxymorphone-3-glucuronide)

• Causes spectrum of symptoms ranging from mild confusion or drowsiness to hallucinations, delirium and seizures

• Typically develops on initiation to a week of initiating an opioid or reaching a dose that causes metabolite buildup.

Opioid-induced Opioid-induced NeurotoxicityNeurotoxicity

• Dehydration, infection, or adding drugs that depress the central nervous system can tip a frail older adult into opioid toxicity.

• A patient who has been receiving a stable dose of an opioid for more than 2 weeks is unlikely to develop OIN unless precipitated by dehydration, infection, or a drug interaction.

• OIN is managed by opiod rotation, dose or frequency reduction and rehydration.

• Opioids should not be discontinued if they are needed for pain or dyspnea.

Antinociceptive Tolerance

• Is a pharmacologic concept• Due to prolonged use of opiates• It occurs when there is a progressive

lack of response to a drug requiring increased dosing

• Higher doses of opiates are required to elicit same amount of analgesia or antinociception

The mechanism by which prolonged opiate exposure

induces hyperalgesia and the relationship of this state to antinociceptive tolerance

remain unclear

Opioid Induced Opioid Induced HyperalgesiaHyperalgesia

Opioid Induced Opioid Induced HyperalgesiaHyperalgesia

• Hyperalgesia and allodynia• Myoclonus• Confusion• Related to but different from tolerance• Different from opioid neurotoxicity• Has been observed and documented in

literature since 19th century (Observed by Albutt in 1870)

Tolerance vs Opioid Induced Hyperalgesia

• OIH cannot be overcome by increasing dosage

• OIH is a form of pain sensitization induced by opiates which occurs in the CNS

• Pain is worsened with increased opioid dosing

• Pain is improved by reducing/eliminating opioid

• OIH occurs at a certain critical opioid dose (may be lower in patients with renal dysfunction)

• OIH is often overlooked as a potential complication of opioid therapy

Opioid Induced Opioid Induced HyperalgesiaHyperalgesia

• Results from prolonged opiate exposure• Causes sustained neuroplastic changes

in the spinal cord• Results into upregulation of spinal

dynorphin and CGRP (proposed mechanism)

• Activity of opiates at the mu receptor results to activation of NMDA receptors resulting into this state of hyperalgesia

OIH Treatment OIH Treatment StrategiesStrategies

• Challenge patient with an increased opioid dose and evaluate for increased efficacy (tolerance)

• Increased opioid dose will lead to increased pain while a reduction or elimination of opioid dose may improve pain in OIH

• Utilize opioids with unique properties that may mitigate OIH

• Utilize NMDA antagonists

• Respite sedation with propofol?

• Interventional pain techniques or neurosurgical procedures

Opioids with Unique Properties that may Mitigate

OIH• Methadone

– Mu agonist and NMDA antagonist– A racemic mixture in which the d-

isomer is the NMDA antagonist– Displays incomplete cross tolerance

properties– Anecdotal reports show improvement or

control of OIH when reducing opioid dose and adding low dose methadone

MethadoneMethadone

• Can be used to treat OIH• Methadone can relieve opioid

withdrawal• Due to long half life there are fewer

variations in plasma levels• Standard of treatment for opioid

dependence for over 40 years• Methadone can also cause OIH?

Case #1 74 y/o with Case #1 74 y/o with pancreatic cancerpancreatic cancer

• Started on Duragesic patch progressively titrated to 150 mcg

• Had worsening myoclonus, no confusion, no hallucinations

• Progressively worsening pain• Shifted to Dilaudid PCA. Dose

titrated to 2 mg per hour basal and 1 mg q 10 minutes demand. Pain was controlled, myoclonus resolved.

Case # 2 74 y/o with Case # 2 74 y/o with progressive malignant progressive malignant lumbosacral plexopathylumbosacral plexopathy

• On morphine ER 200 mg TID which was progressively titrated to 1000 mg q QID

• Had progressive pain then developed delirium and myoclonus

• Hospitalized and started on Dilaudid PCA that controlled pain for a few days. Upward titration to 25 mg per hour and 10 mg q 10 minutes

• Had progressive delirium, myoclonus and pain

• Dilaudid basal dose was stopped, demand dose was decreased to 5 mg q 10 minutes. Methadone 10 mg QID was started

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