Opioids A to Z

Opioids A to Z Thomas B. Gregory, PharmD, BCPS, DASPE, CPE

Disclosure

Nothing to Disclose

Learning Objectives Recognize patient and medication variables which can impact opioid therapy management Formulate dosing strategies for initial, maintenance and conversions of opioid regimens Identify possible side effects from opioids

Recognize patient and medication variables which can impact opioid therapy management

Variables in Opioid Therapy Medication variables –opioid • pure agonists and partial agonists

–formulation

Patient variables –age, muscle mass, co-morbidities –analgesic tolerance

Are variables constant or can they change?

Medication Variables Mechanism of action (MOA) and side effects –opiates work at multiple receptors • Mu

µ1 : analgesia µ2 : side effects • Kappa (mixed) • Delta (mixed)

methadone - NMDA receptor antagonist tapentadol – mu opioid agonist and norepinephrine reuptake inhibitor

Medication Variables (cont’d) Pure agonists versus partial agonists –pure agonists have no ceiling effect related to analgesia –partial agonists will plateau analgesia despite increases in dose

Strong versus weak opioids –codeine –tramadol

Medication Variables (cont’d)  Opioid dose formulation – formulation can have an impact on onset and duration of analgesia

 Cost – not just related to the co-pay

 Pharmacokinetics and side effects differ between opioid families and individual medications

Medication Pharmacokinetics  Absorption – tablets, patches, solutions, buccal tablet, etc.

 Distribution – hydrophilic versus lipophilic

 Metabolism – active metabolites, prodrugs, etc.

 Elimination – renal, hepatic, stool, other

Formulation Variables Short acting opioids –parenteral and enteral administration –not subject to REMS criteria in 2012 –initial opioid dosing strategies use short acting opioids either on an as needed basis or around the clock fashion –start low and go slow regarding upward dose titration REMS = risk evaluation and mitigation strategies

Formulation Variables (cont’d)  Long acting opioids – enteral and transdermal administration – subject to REMS programs – generally started after dose finding strategy with short acting opioids are complete – these formulations minimize peaks and valleys associated with analgesia and side effects – appropriate for patients with persistent pain REMS = risk evaluation and mitigation strategies

Formulation Variables (cont’d) Rapid onset opioids –transmucosal administration –subject to an umbrella REMS program for all agents –these agents are appropriate for patients tolerant to opioids –these agents adequately manage break though pain when used in concert with long and short acting opioids REMS = risk evaluation and mitigation strategies

Patient Variables Age and race Renal and hepatic function Body habitus History of responsiveness to opioid therapy –toxic –therapeutic

Patient Variables (cont’d)  Allergies, sensitivities and drug interactions  Co-morbidities – gastroparesis – substance abuse

 Cognitive status  Self administration of opioids – dexterity – enteral administration

Patient Variables (cont’d)  Work, life and time balance  Health beliefs – misconceptions – fear

 Social support system – positive and negative

Families of opioids Phenanthrenes Phenylpiperidines Diphenylheptanes

Phenanthrenes  Codeine – Commonly associated with cough suppression instead of pain management – weak opioid agonist compared to morphine • approximately 1/6th potency

– for moderate pain or cough associated with pain

 Codeine is metabolized into morphine primarily by CYP 2D6 – poor metabolizers will not receive the analgesic effects – SSRI’s and other inhibitors of CYP 2D6 can block the analgesic effects CYP = cytochrome P450 enzyme SSRI = select serotonin reuptake inhibitors

Phenanthrenes (cont’d)  Morphine: gold standard for opioids – most opioid equianalgesic conversion tables use morphine as a fulcrum point – multiple routes of administration and sustained release formulation are available

 Morphine has active metabolites – caution in patients with kidney or liver dysfunction as the metabolites can accumulate resulting in side effects

Phenanthrenes (cont’d)  Hydrocodone: most widely prescribed medication in the United States in 2010 – hydrocodone is metabolized into hydromorphone – approximately equianalgesic to oral morphine on a milligram basis – currently all hydrocodone products are combined with acetaminophen or non-steroidal agents – caution in patients taking other acetaminophen products or with liver disease

Phenanthrenes (cont’d) Hydromorphone: most potent on a milligram basis within the phenanthrene family –hydromorphone 2 mg IV is equivalent to hydromorphone 7.5 mg oral formulation and approximately 10 mg IV morphine –the 2011 updated package insert indicates the initial IV dosing range for patients naive to opioids as 0.2 mg to 1 mg* • due to incorrect dosing conversions leading to serious adverse events http://www.purduepharma.com/PI/prescription/DilaudidInjectionsPI.pdf. Accessed June 2, 2012

Phenanthrenes (cont’d)  Oxycodone – oxycodone is converted to oxymorphone; both components are strong opioid agonists – oxycodone is 50% the potency of oxymorphone in terms of analgesic activity – available formulations • in combination with acetaminophen or other adjuvant • immediate release • sustained release

Phenanthrenes (cont’d)  Oxymorphone – three times the potency of oral morphine on a milligram basis – available in immediate and extended release oral formulations only – advantages over oxycodone include a decreased incidence of nausea

Phenylpiperidine  Meperidine- prototypic agent in the family – meperidine 75 mg IV is equivalent to morphine 10 mg IV – duration of analgesia is much less than morphine – caution in renal failure as active metabolites can accumulate – side effects can include seizures in addition to standard opioid side effects • seizures are NOT reversible with naloxone • antiseizure medications are the standard management of nor-meperidine seizures

Phenylpiperidine (cont’d)  Fentanyl – multiple formulations available • transmucosal formulations have rapid onset and are used in managing break though pain – these formulations are NOT interchangeable

• transdermal formulations require 12 hours on the skin for onset of analgesia – during initial patch application ensure adequate break though opioids are available to the patient

– no biologically active metabolites

Diphenylheptanes  Methadone: used in the management of opioid withdrawal and acute or chronic pain – methadone has extremely variable kinetics • half-life range from 3 to 103 hours

– methadone can be safely used for pain management when dosed every eight to twelve hours – methadone has multiple drug interactions

Opioid tolerance threshold  Patients taking the following total daily dose of opioid – oral morphine 60 mg/day – transdermal fentanyl 25 mcg/hour – oral oxycodone 30 mg/day – oral oxymorphone 25 mg /day – oral hydromorphone 8 mg/day

Formulate dosing strategies for initial, maintenance and conversions of opioid regimens

Oral Opioid Initiation Dosing Oral morphine – 2.5-5 mg every 4 hours Oral hydromorphone – 1-2 mg every 3-4 hours Oral oxycodone – 2.5-5 mg every 4 hours For patients not in an acute pain crisis For patients that are naïve to opioids

Dose-Finding Around-the-Clock Opioid Therapy  Most patients start with as needed dosing  Pick your starting dose of morphine, oxycodone or hydromorphone for around the clock therapy – the same dose of opioid should be available for break through pain every 1-2 hours

 Have patient keep a pain diary – pain effectively controlled – development of side effects around dosing frequency

Reasons for Changing Opioids  Lack of therapeutic response  Development of adverse effects  Change in patient condition  Other considerations – opioid/formulation availability – formulary issues – patient/family healthcare beliefs

Equianalgesic Dosing Many opioid equianalgesic conversion charts exist in the literature These should serve as a guide not as gospel to conversion Cross tolerance is not universal in nature –acute pain crisis, conversion without accounting for cross tolerance –when pain is controlled cross tolerance should be taken into account

Opioid Conversion Chart Example Opioid analgesic  Morphine  Hydromorphone  Oxycodone  Hydrocodone  Fentanyl  Oxymorphone  Codeine

Oral Parenteral 30 mg 10 mg 7.5 mg 2 mg 20 mg NA 30 mg NA NA 100 mcg 10 mg NA 180 mg 120 mg

Mechanisms of Analgesic Tolerance  Pharmacokinetic – Through alteration of metabolism • Methadone initiation (induction) • Known metabolic enzyme inhibitors

 Pharmacodynamic – Decrease in opioid response • Up-regulation of opioid receptors

 Cross tolerance – Tolerance to a specific opioid that does not translate into the same opioid effect given equianalgesic dosing

5-Step OCC Process 1. Globally assess pain complaint 2. Determine total daily dose (TDD) current opioid (LA and SA) 3. Decide which opioid analgesic will be used for the new agent and consult established conversion tables to determine new dose 4. Individualize dosage based on assessment information gathered in Step 1 5. Patient follow-up and continual reassessment (7-14 days) OCC = Opioid conversion calculation LA = long-acting SA = short-acting Gammaitoni AR, et al. Clinical J Pain. 2003;19:286-297.

Switching from SA to LA (same opioid) 1. Globally assess pain complaint 2. Determine TDD current opioid (SA) 3. Decide which opioid analgesic will be used for the new agent and consult established conversion tables to determine new dose • Same opioid, same route of administration, no ratio calculation needed

4. Individualize dosage based on assessment information gathered in Step 1 5. Patient follow-up and continual reassessment (7-14 days) OCC = Opioid conversion calculation LA = long-acting SA = short-acting

Opioid Dosage Escalation Strategies  For moderate to severe pain, increase opioid TDD by 50%100%, regardless of starting dose  For mild to moderate pain, increase opioid TDD by 25%-50%, regardless of starting dose  SA, immediate-release single-ingredient opioids (morphine, oxycodone, hydromorphone) can be safely dose-escalated every 2 hours  LA, sustained-release opioids can be increased every 24 hours (this does not include transdermal fentanyl or methadone) OCC = Opioid conversion calculation LA = long-acting SA = short-acting

Switching from One Oral Opioid to Another Oral Opioid Must consider equipotent ratio from equianalgesic dosing chart Consider bioequivalence between routes of administration Follow 5-step opioid conversion process Consider lack of complete cross-tolerance

Setting up the Conversion Equation  Calculate total daily dose of current opioids  Set up conversion ratio between old opioid (and route of administration) and new opioid (and route of administration) as follows: x mg new opioid = equivalent mg new opioid mg of current opioid equivalent mg current opioid

Solving the Equation Cross multiply, solve for “x” Individualize dose for patient –Pain controlled –Developed adverse effects –Identification of peaks and valleys

Case  Mr. Jones is a 65 year old male with prostate cancer, currently receiving morphine extended release 90 mg po q12h and morphine solution 30 mg po q4h prn, taking on average 3 doses per day  He’s been on this dose for about 2 weeks, and the pain is well controlled, but he’s developed visual hallucinations, which concern him and his family

Case (cont’d) He has significant renal impairment (serum creatinine of 2 mg/dL) and this adverse effect may be due to accumulation of morphine metabolites His physician would like to switch to long-acting oxycodone What are the steps necessary to make this conversion?

Case (cont’d) “x” mg new opioid = equivalent mg new opioid mg of current opioid equivalent mg current opioid “x” mg new opioid = 20 mg (oxycodone) 270 mg morphine 30 mg (morphine) (x)(30) = (20)(270) X = 180 mg oral oxycodone per day

Case  Since his pain is controlled decrease the conversion dose by 50% to account for cross tolerance – 90 mg oxycodone in 24 hours

 Oxycodone extended release comes in 15 mg tablets, 3 tabs (45 mg) every 12 hours  Breakthrough oxycodone 10 mg every 2 hours as needed  Reassess in 48 hours if adjustments are needed

Pharmacokinetics of IR Opioids Solubility

IR Opioids

Onset of analgesia

Duration of effect

Hydrophilic

Morphine (oral)

30-40 minutes

4 hours

Oxycodone (oral)

30 minutes

4 hours

Oxymorphone (oral)

30 minutes

4-6 hours

Hydromorphone (oral)

30 minutes

4 hours

Methadone (oral)

10-15 minutes

4-8 hours

Fentanyl (transmucosal)

5-10 minutes

1-2 hours

Lipophilic

IR = immediate release Bennett D, et al. P&T. 2005;30:354-361.

When Do You Increase the Long-Acting Opioid? Patients using multiple doses of break though/rescue opioid doses –Only consider doses used for slow-onset idiopathic pain in calculations –When two or more doses of rescue are used daily, consider increasing the long-acting opioid

As you increase the long-acting opioid, increase the rescue opioid as well

Identify possible side effects from opioids

Physiologic Effects  Neurologic  Cardiovascular  Pulmonary  Gastrointestinal  Endocrine  Integumentary  Genitourinary

Sedation Primarily in opioid naive patients –Effects mediated by anticholinergic activity of opioids –Generally transitory in nature and resolve within one week after stable opioid dosing

If sedation persists or is not addressed it can lead to noncompliance and decreased quality of life

Psychomotor  Opioids can slow reaction time  Warnings on most prescriptions include cautions for driving or operating heavy machinery  Review of patients receiving stable doses of opioids did not have impairment of driving-related skills*

Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS. Are opioid-dependent/ tolerant patients impaired in driving related skills? A structured evidence based review. J Pain Symptom Manage 25:559-577 2003

Cognition Opioids have been linked to alterations in cognition The changes are associated with both acute and chronic opioid use –More commonly associated changes include • Disorientation • Agitation • Confusion • Hallucinations

Hyperalgesia Increase in sensitivity to noxious stimulus –Dose escalation can lead to no change in analgesia or worsening pain

Associated with long term utilization of opioids –Thought to be associated with neuroexcitatory receptors • NMDA • AMPA

Arrhythmia  Torsades de pointes – Associated with methadone more frequently compared to other opioids • Prospective data from cancer patients on methadone • 8% had an increase in QTc on ECG tracing and one patient had a QTc > 500 ms • Data suggest methadone can be safely used regardless of baseline ECG* – Highly encouraged to have baseline and routine electrolyte measurements

Reddy S. Hui D. El Osta B. de la Cruz M. Walker P. Palmer JL. Bruera E. The effect of oral methadone on the QTc interval in advanced cancer patients: a prospective pilot study. Journal of Palliative Medicine. 13;1:33-8, 2010

Respiratory Depression Patients naive to opiates are at an increased risk –Direct effect on the medulla decreasing cough and respiratory drive

Patients with COPD, obesity and recent abdominal surgery are at higher risk in the acute setting Neonatal and elderly are also more sensitive to opioids placing them at an increased risk

Constipation Most common side effect of opioid use Inhibition of the enteric nervous system causes –Decrease in propulsion and secretion though the GI tract –Decrease in intestinal motility –Increased transit time in the large bowel leading to increase in water absorption

Nausea and Vomiting Nausea is induced by stimulation of the chemotactic center in the brain and a decrease in gastrointestinal motility Risk factors include –Female > Male –Caucasian < African descent

Transitory in nature occurring at initiation of opioids and with dose escalations

Sphincter of Oddi Meperidine has been long reported to not cause an increase in sphincter of Oddi pressure All opioids (including meperidine) cause an increase in the sphincter of Oddi pressure* Results suggest partial agonists such as nalbuphine and buprenorphine may be acceptable alternatives

Isenhower HL. Selection of narcotic analgesics for pain associated with pancreatitis. American Journal of Health systems Pharmacy 55;5:480-6 1998

Hormonal Imbalance Primarily among long term opioid users Opioids result in decreases in –Testosterone, estrogen and the sex hormone precursors luteinizing hormone and gonadotropin releasing hormone

These decreases have been associated with –Decreased libido, sexual dysfunction, decreased energy

Hormonal Imbalance (cont’d) Increased risk for osteoporosis – 8000 + Caucasian females over 65 in a study observing fracture rates related to central nervous system active medications – Patients on “narcotics” had a two fold increase in relative risk for developing non-spine fractures – After age-adjustment and multiple correction factors relating to narcotic use (sedation, gait, etc) there was still an increase in fractures by a hazard ratio of 1.4

Ensrud KE, Blackwell T, Mangione CM, Bowman PJ, Bauer DC, Schwartz A, Hanlon JT, Nevitt MC, Whooley MA. Study of Osteoporotic Fracture Research Group.

Central nervous system active medications and risk for fractures in older women. Arch Intern Med 163:949-957 2003

Immune suppression  Many opioids have immunosuppressive properties – Morphine has been linked to inhibition of* • Antibody and cellular immune response • Natural killer cell activity • Cytokine activity • Phagocytic activity

– One hypothesis is through activation of the hypothalamic-pituitaryadrenal (HPA) axis

Stefano GB. Endogenous opiates, opioids, and immune function: Evolutionary brokerage of defensive behaviors. Seminars in Cancer Biology 18: 190–198 2008

Immune suppression (cont’d)  Activation of the HPA axis has shown to increase circulating cortisol, decreasing inflammatory and immune function  Management strategies include opioid rotation – Methadone1, tramadol2, and buprenorphine3 had no effect on immune function

 No clinical significance has been observed from the immune suppression exerted by opioids 1. Pacifici R, et. al. Effect of Morphine and Methadone Acute Treatment on Immunological Activity in Mice: Pharmacokinetic and Pharmacodynamic Correlates. Journal of Pharmacology & Experimental Therapeutics. 269;3:1112-6 1994 2. Sacerdote P, et al. The Effects of Tramadol and Morphine on Immune Responses and Pain After Surgery in Cancer Patients. Anesthesia and analgesia 90;6: 1411-4 2000.

3. Gomez-Flores, R. Differential effects of buprenorphine and morphine on immune and neuroendocrine functions following acute administration in the rat mesencephalon periaqueductal gray. Immunopharmacology 48: 145–156 2000

Urinary Retention Mechanism of urinary retention with opioids is not completely understood –Opioids have been associated with decreases in •Detrusor muscle tone •Force of detrusor contraction •Sensation of fullness •Voiding reflex

Pruritus  Likelihood ranges from 2 to 10% of all patients that receive opioids – Increased rate with neuraxially administered opioids; between 30100%

 Mechanism is related to the following neurotransmitters – Histamine – Serotonin – Prostaglandins – Endogenous opioids

Summary Opioid therapy depends on multiple variables some of which change in the middle of therapy Opioid conversion charts are available and should be consulted when changing opioid therapy Opioid side effects can be managed though slow dose titration or opioid rotation

References http://www.purduepharma.com/PI/prescription/DilaudidInjectionsPI.pdf. Accessed June 2, 2012 LA, long-acting; SA, short-acting. Gammaitoni AR, et al. Clinical J Pain. 2003;19:286-297 Bennett D, et al. P&T. 2005;30:354-361 Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS. Are opioid-dependent/ tolerant patients impaired in driving related skills? A structured evidence based review. J Pain Symptom Manage 25:559-577 2003 Reddy S. Hui D. El Osta B. de la Cruz M. Walker P. Palmer JL. Bruera E. The effect of oral methadone on the QTc interval in advanced cancer patients: a prospective pilot study. Journal of Palliative Medicine. 13;1:33-8, 2010 Isenhower HL. Selection of narcotic analgesics for pain associated with pancreatitis. American Journal of Health systems Pharmacy 55;5:480-6 1998 Ensrud KE, Blackwell T, Mangione CM, Bowman PJ, Bauer DC, Schwartz A, Hanlon JT, Nevitt MC, Whooley MA. Study of Osteoporotic Fracture Research Group. Central nervous system active medications and risk for fractures in older women. Arch Intern Med 163:949-957 2003 Stefano GB. Endogenous opiates, opioids, and immune function: Evolutionary brokerage of defensive behaviors. Seminars in Cancer Biology 18: 190â&#x20AC;&#x201C; 198 2008 Pacifici R, et. al. Effect of Morphine and Methadone Acute Treatment on Immunological Activity in Mice: Pharmacokinetic and Pharmacodynamic Correlates. Journal of Pharmacology & Experimental Therapeutics. 269;3:1112-6 1994 Sacerdote P, et al. The Effects of Tramadol and Morphine on Immune Responses and Pain After Surgery in Cancer Patients. Anesthesia and analgesia 90;6: 1411-4 2000.

Gomez-Flores, R. Differential effects of buprenorphine and morphine on immune and neuroendocrine functions following acute administration in the rat mesencephalon periaqueductal gray. Immunopharmacology 48: 145â&#x20AC;&#x201C;156 2000