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Guidelines

Appendix C – Opioid Pharmacology

Names of medications

  • Naturally occurring opioids: codeine, morphine
  • Semi-synthetic opioids: hydrocodone, hydromorphone, oxycodone, oxymorphone, buprenorphine
  • Semi-synthetic opioids: meperidine, fentanyl, methadone, tramadol, tapentadol

(Pathan, 2012; Trescot, 2008)

Indication

Severe acute pain and chronic pain related to cancer (Chou, 2009a).

The FDA has announced class-wide safety labeling changes for immediate release (IR) opioids due to the risks associated with opioid medications. “The updated indication clarifies that because of these risks, IR opioids should be reserved for pain severe enough to require opioid treatment and for which alternative treatment options (e.g., non-opioid analgesics or opioid combination products, as appropriate) are inadequate or not tolerated.” For additional information, please refer to http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm491739.htm - Press release.

General mechanism of action

Opioids bind to mu, delta and kappa opioid receptors on the presynaptic terminals of the nociceptive C-fibers and A delta fibers inhibiting the release of pain neurotransmitters (Trescot, 2008). Opioids also activate presynaptic receptors on GABA neurons inhibiting the release of GABA and promoting extra dopamine release (Trescot, 2008). Unlike other modalities, opioids have no ceiling effect on pain relief, but use is limited by the development of adverse effects (Pasternak, 2014).

Common adverse effects

  • The most common side effects of opioids are nausea and constipation (Benyamin, 2008).
  • Additional side effects include vomiting, pruritus, sedation, physical dependence, tolerance, respiratory depression, euphoria, dysphoria, miosis, urticaria and hypotension (Benyamin, 2008).

The FDA released a safety communication warning requiring changes to be made to the labels of all opioid medications warning about the risks of serotonin syndrome, adrenal gland insufficiency and reduced sex hormone levels. For additional information, please refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm491715.htm.

Absolute contraindications

Absolute contraindications to opioids include severe respiratory instability, acute psychiatric instability or uncontrolled suicide risk, diagnosed non-nicotine substance use dismedication drug capable of inducing life-limiting drug-drug interactions, QTc interval longer than 500 milliseconds if prescribed methadone, acute diversion of controlled substances and prior adequate trials of specific opioids that were discontinued due to intolerance, serious adverse effects or lack of efficacy (U.S. Department of Veterans Affairs, 2010).

Hepatic/renal dosing

Opioid pharmacokinetics depends on patient-related factors as well as the chemical properties of each opioid (Gelot, 2014). Hepatic or renal insufficiency may change the pharmacokinetic properties of opioids complicating treatment (Gelot, 2014). Please refer to the following charts for recommendations about using opioids in patients with hepatic or renal insufficiency.

Opioid Utilization

Oral morphine milligrams equivalent (MME) doses are increasingly being used as a metric to represent opioid use (Nielsen, 2016). MMEs are based on the idea that different doses of different opioids may produce a similar analgesic effect (Nielsen, 2016). The following table depicts MMEs for the most commonly used opioids. Of note, methadone has a complicated pharmacokinetic and pharmacodynamic profile with a variable MME ratio (Chou, 2009a). Initiating a patient on methadone should be reserved for experienced clinicians who are familiar with its use (Chou, 2009b).

Whether data is presented at the individual (patient) level or in total, the recommended conversion factors can be used to convert a given dose/amount of an opioid to MMEs using the following formula: strength per unit × (number of units/day (or total)) × MME conversion factor = MME units per day (or total) (Nielsen, 2016).

MME conversion examples

  • A patient is taking Oxycontin 30 mg three times a day: 30 mg x 3 doses/day x conversion factor of 1.5 = 135 mg MME/day.
  • A patient is using a 25 mcg fentanyl patch every three days: 25 mcg x 1 patch/day x conversion factor of 2.7 = 67.5 mg MME/day.
  • A patient received a quantity of fifteen Tramadol 100 mg tablets: 100 mg x 15 tablets x conversion factor of 0.2 = 300 mg MME total.

It should be noted these calculations are only intended to convert an opioid to morphine equivalents (Nielsen, 2016). Different conversion factors may be necessary when converting to an opioid other than morphine (Nielsen, 2016).

Opioid Rotation

* http://www.cancer.gov/about-cancer/treatment/side-effects/pain/pain-hp-pdq#link/_63_toc(Pharmacist’s Letter/Prescriber’s Letter, 2014; Chou, 2009a)

Naturally Occurring Opioids

Codeine: (MME = 0.1)

Indication: Mild to moderate pain (Codeine package insert, 2015)

Additional Mechanism(s) of Action: None

Specific Adverse Effects: None

Precautions/contraindications

  • The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for the CYP2D6 genotype recommend avoiding use in known ultra-rapid metabolizers (1-2% of patients) or poor metabolizers (5-10% of patients) (Crews, 2014).
  • Use in renal failure and dialysis is not recommended due to the accumulation of active metabolites (Dean, 2004).
  • In 2007, the FDA identified that infants of nursing mothers taking codeine may have an increased risk of morphine overdose if the mother is an ultra-rapid metabolizer of codeine. When prescribing codeine to nursing mothers, physicians should choose their lowest dose for the shortest period of time and should closely monitor mother-infant pairs. For more information, refer to http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124889.
  • The FDA added a black box warning in 2013 recommending alternative9.htm analgesics for children undergoing tonsillectomy and/or adenoidectomy. Respiratory depression and death have occurred in children with evidence of cytochrome P450 2D6 polymorphism. For more information, refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm315627.htm. The FDA is currently evaluating the safety of codeine for cough in children under the age of 18 due to potential serious side effects. For more information, refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm453379.htm.

Additional information

  • Available alone or in combination with acetaminophen. (Micromedex).
  • Metabolized to codeine-6-glucuronidide, to the active metabolite morphine by cytochrome P450 2D6 and norcodeine by CYP3A4 (Codeine package insert, 2015).

Morphine: (MME oral = 1, MME IV = 3)

Indication: Moderate to severe pain (Morphine package insert, 2012).

Additional mechanism(s) of action: None

Specific adverse effects

  • May cause severe hypotension and elevated intracranial pressure (Morphine package insert, 2012).

Precautions/contraindications

  • Use in renal failure and dialysis is not recommended due to the accumulation of active metabolites (Dean, 2004).

Additional information

  • Available in injectable, rectal, rapid-acting oral, 12-hour sustain release and 24 hours sustained-release oral formulations (Micromedex).
  • Metabolized by glucuronidation to an active metabolite morphine-6-glucuronide and the inactive morphine-3-glucuronide (Morphine package insert, 2012).

Semi-Synthetic Opioids

Hydrocodone (MME = 1)

Indication: Moderate to moderately severe pain (Norco package insert, 2014) or pain severe enough to require around-the-clock opioid treatment when alternative therapies are inadequate (Zohydro package insert, 2015; Hyslinga package insert, 2014).

Additional mechanism(s) of action: None

Specific adverse effects

  • QTc prolongation has been observed when daily doses of Hyslinga exceed 160 mg/day (Hyslinga package insert, 2014).

Precautions/contraindications

  • Contraindicated in patients with acute or severe bronchial asthma in unmonitored settings or without resuscitative equipment (Zohydro package insert, 2015; Hyslinga package insert, 2014).
  • Use Zohydro cautiously in patients with severe hepatic and renal impairment (Zohydro package insert, 2015).
  • Norco should be used cautiously during pregnancy only if the potential benefits outweigh the potential risks (Norco package insert, 2014).
  • May cause fetal harm or neonatal opioid withdrawal syndrome (NAS) if used during pregnancy (Zohydro package insert, 2015).
  • Use during lactation is not recommended (Zohydro package insert, 2015).

Additional information

  • Available in combination with acetaminophen (Norco package insert, 2014) or alone as a twice-daily extended-release product (Zohydro package insert, 2015) or a once-daily extended-release product (Hyslinga package insert, 2014).
  • Hydrocodone is metabolized primarily by CYP2D6 to the active metabolite hydromorphone and by CYP3A4 to inactive metabolize norhydrocone. CYP3A4 inhibitors, or discontinuation of CYP3A4 inducers, may cause elevated hydrocodone concentrations prolonging adverse effects and respiratory depression (Norco package insert, 2014).
  • Zohydro and Hyslinga must be swallowed whole (Zohydro package insert, 2015; Hyslinga package insert, 2014).
  • Currently there are no recommendations for converting from Zohydro or Hyslinga to an alternative opioid (Zohydro package insert, 2015; Hyslinga package insert, 2014).

Hydromorphone (MME oral = 4, MME IV = 17.5)

Indication: Moderate to severe pain (Dilaudid package insert, 2015).

Additional mechanism(s) of action: None

Specific adverse effects:

  • May cause severe hypotension and elevated intracranial pressure (Dilaudid package insert, 2015).

Precautions/contraindications

  • Exalgo is contraindicated in opioid-naïve patients and patients with moderate to severe hepatic impairment (Exalgo package insert, 2015).
  • Hydromorphone should be used carefully in renally impaired and dialysis patients (Dilaudid package insert, 2015).
  • Exalgo is not recommended for patients with severe renal impairment (Exalgo package insert, 2015).

Additional information

  • Available in injectable, rectal and both rapid-release (Dilaudid package insert, 2015) and once-a-day extended-release oral dosage forms (Exalgo package insert, 2015).
  • Primarily metabolized into inactive metabolite hydromorphone-3-glucornide (Dilaudid package insert, 2015).
  • Exalgo must be swallowed whole (Exalgo package insert, 2015).
  • Ghost capsules may be visible in stool (Exalgo package insert, 2015).

Oxycodone (MME = 1.5)

Indication: Moderate to moderately severe pain (Oxycodone package insert, 2014).

Additional mechanism(s) of action: None

Specific adverse effects: None

Precautions/contraindications:

  • Use cautiously in patients with severe renal impairment (Dean, 2004).
  • Concomitant use of CYP3A4 inhibitors, such as macrolide antibiotics (e.g., azithromycin), azole-antifungal agents (e.g., ketoconazole) and protease inhibitors (e.g., ritonavir) may result in increased oxycodone concentrations and subsequent adverse effects. Concurrent use with CYP3A4 inducers, such as phenytoin and carbamazepine, may result in decreased oxycodone concentrations or lack of efficacy (Oxycodone package insert, 2014).

Additional information:

  • Available in combination with acetaminophen or alone as a short-acting or long-acting oral dosage form (Micromedex).
  • Metabolized by CYP3A4 to the active metabolite noroxycodone and by CYP2D6 to the active metabolite oxymorphone (Oxycodone package insert, 2014).

Oxymorphone (MME oral = 3, MME IV = 30)

Indication: Moderate to severe pain (Oxymorphone package insert, 2014) and for the relief of moderate to severe pain in patients requiring continuous around-the-clock opioid treatment for chronic pain (Opana ER package insert, 2012). Oxymorphone ER is not indicated for acute pain (Opana ER package insert, 2012).

Additional mechanism(s) of action: None

Specific adverse effects:

  • May increase intracranial pressure (Oxymorphone package insert, 2014).

Precautions/contraindications:

  • Use in patients with moderate to severe hepatic dysfunction is contraindicated (Oxymorphone package insert, 2014).
  • Use cautiously in patients with severe renal impairment (Oxymorphone package insert, 2014).

Additional information

  • Available as an injectable, immediate-release (Oxymorphone package insert, 2014) and extended-release oral formulations (Opana ER package insert, 2012).
  • Metabolized to active metabolite 6-OH-oxymorphone and an inactive metabolite oxymorphone-3-glucoronide (Oxymorphone package insert, 2014).
  • No dosage conversions are available for converting from oxymorphone ER to another opioid (Opana ER package insert, 2012).
  • Oxymorphone ER tablets must be swallowed whole (Opana ER package insert, 2012).

Buprenorphine (MME = 2.2)

Indication: Indicated for the management of pain severe enough to require around-the-clock opioid treatment when alternative therapies are inadequate (Butrans package insert, 2014).

Additional mechanism(s) of action: Partial agonist at the mu and ORL-1 receptors, a full agonist at the delta opioid receptor and an antagonist at the kappa opioid receptor (Butrans package insert, 2014).

Specific adverse effects

  • QTc prolongation at doses exceeding 20 mcg/hour (Butrans package insert, 2014).

Precautions/contraindications

  • Accidental exposure to even one dose, especially in children, may be fatal (Butrans package insert, 2014).
  • Butrans 20 mcg/hour may not provide adequate analgesia for patients requiring > 80 MME/day (Butrans package insert, 2014).
  • Butrans has not been evaluated in patients with severe hepatic toxicity (Butrans package insert, 2014).
  • Avoid use in patients with a history of prolonged QTc (Butrans package insert, 2014).

Additional information

  • Patches are changed once weekly and should not be reapplied to the same site within three weeks (Butrans package insert, 2014).
  • Opioid-naïve patients and patients requiring < 30 mg of MME/day should be initiated with a 5 mcg/hour patch. Patients requiring 30-80 MME/day should be initiated with a 10-mcg/hour patch (Butrans package insert, 2014).
  • Do not apply heat directly to the patch as an increase in absorption may occur (Butrans package insert, 2014).
  • Do not use if patch is cut and do not cut the patch (Butrans package insert, 2014).
  • Patch disposal – Place patch in disposal unit or fold the adhesive side on itself and flush down the toilet (Butrans package insert, 2014).

Synthetic Opioids

Meperidine (MME 0.4)

Indication: Moderate to severe pain (Meperidine package insert, 2016).

Additional mechanism(s) of action: None

Specific adverse effects

  • May increase intracranial pressure and aggravate preexisting convulsions (Meperidine package insert, 2016).

Precautions/contraindications

  • Concurrent use of MAOIs, or use within the last 14 days, is contraindicated (Meperidine package insert, 2016).
  • Avoid use in severe renally impaired patients (Meperidine package insert, 2016).

Additional information

  • Available in oral and injectable formulations (Micromedex).
  • Metabolized by N-demethylation to active metabolite normeperidine, which has 2-3 times the CNS effects of meperidine (Meperidine package insert, 2016).
  • Use is limited to 48 hours and dose should not exceed 600 mg/24 hours due to the metabolite normeperidine (Berry, 2001).
  • The American Pain Society (2008) and ISMP (2007) do not recommend meperidine’s use as an analgesic.
  • Oral route is not recommended for acute or severe pain (Berry, 2001).
  • Meperidine is not recommended for the treatment of chronic pain due to bioaccumulation and adverse effects (Hegmann, 2014).

Fentanyl (MME IV = 0.2, MME transdermal = 2.7)

Indication: Transdermal fentanyl is indicated for the management of pain in opioid-tolerant patients (Duragesic package insert, 2014).

Transmucosal immediate-release fentanyl (TIRF) products (buccal tablets, sublingual tablets, transmucosal lozenges, nasal spray, buccal soluble film and sublingual spray) are indicated for the management of breakthrough cancer pain in those who are already tolerant on regular opioid therapy (TIRF Education Program).

Specific adverse effects: None

Precautions/contraindications

  • Avoid use in patients with severe renal and hepatic impairment (Duragesic package insert, 2014).
  • CYP3A4 inhibitors, or discontinuation of CYP3A4 inducers, may result in a fatal overdose from the transdermal patch (Duragesic package insert, 2014).

Additional information

  • Available as injectable, transdermal and transmucosal immediate-release products (Micromedex).
  • Metabolized by CYP3A4 to inactive metabolites (Duragesic package insert, 2014).
  • Patches are applied every 72 hours, although some patients may require patches to be applied every 48 hours (Duragesic package insert, 2014).
  • Kinetics – Fentanyl levels increase gradually between 12 and 24 hours after the patch has been applied. Significant amounts of fentanyl continue to be absorbed 24 hours or more after a patch has been removed. Seventeen or more hours are required for a 50% reduction in serum fentanyl concentrations after patch has been removed (Duragesic package insert, 2014).
  • Avoid exposure of fentanyl patch to direct heat. Heat increases the release of fentanyl in a temperature dependent manner (Duragesic package insert, 2014).
  • Patch disposal – Patches should be disposed immediately after removal by folding stick side on itself and flushing down the toilet. Unused patches should be removed from their liners, folded in half on the adhesive side and flushed down the toilet. Failure of proper disposal of fentanyl transdermal patches has resulted in accidental exposure and deaths (Duragesic package insert, 2014).
  • Despite an FDA-issued Public Health Advisory in July 2005 regarding the appropriate and safe use of the transdermal system, death and life-threatening adverse events related to fentanyl overdose have occurred when the fentanyl patch was used to treat pain in opioid-naive patients and when opioid-tolerant patients have applied more patches than prescribed, changed the patch too frequently, and exposed the patch to a heat source.
  • Directions for prescribing and using the fentanyl patch must be followed exactly to prevent death or other serious side effects from fentanyl overdose.
  • In 2012, the FDA evaluated a series of 26 pediatric accidental exposure to fentanyl patches over 15 years and re-emphasized the importance of appropriate storage, use, application and disposal of fentanyl patches to prevent potentially life-threatening harm from accidental exposure. This is in addition to the previous warnings in 2005 and 2006 following reports of death and life-threatening adverse events related to fentanyl overdose. For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm300747.htm.

Methadone (MME = 4-12)

Indication: Pain severe enough to requiring daily, around-the-clock, long-term opioid treatment (Methadone package insert, 2016).

Additional mechanism(s) of action: The S isomer is an NMDA antagonist and inhibits the re-uptake of norepinephrine and serotonin (Trescot, 2008).

Specific adverse effects

  • QTc prolongation. Cases of serious QT interval prolongation leading to serious arrhythmias have been reported (Methadone package insert, 2016).

Precautions/contraindications

  • Contraindicated with MAOIs or use within 14 days of discontinuing MAOIs (Methadone package insert, 2016).

Additional information

  • Available in injectable and oral formulations in a variety of concentrations (Methadone package insert, 2016).
  • Primarily metabolized by CYP3A4, CYP2B6 and CYP2C19 to inactive metabolize 2-ethylidene-1, 5-dimethyl-3,3-diphenylpyrrolidene (Methadone package insert, 2016).
  • Initiating a patient on methadone requires a cautious and highly individualized approach due to inter-patient differences in the pharmacokinetic properties of the medication. Methadone is highly lipophilic and has a prolonged, but variable, half-life (Methadone package insert, 2016).
  • The analgesic effect lasts 4-8 hours, but the peak respiratory depressant effect occurs later and last longer than the analgesic effects (Methadone package insert, 2016).
  • Steady-state concentrations are attained 3-5 days after initiating therapy (Methadone package insert, 2016).
  • Baseline EKGs are recommended for all patents being initiated on methadone, with follow-up EKGs at 30 days and annually thereafter. More frequent EKG monitoring is recommended for all patients requiring >100 mg/day or those with unexplained syncope and seizures (Krantz, 2009).

Tramadol (MME = 0.2)

Indication: Tramadol immediate release is indicated for the relief of moderate to moderately severe pain (Tramadol package insert, 2012). Tramadol extended-release is indicated for the relief of moderate to moderately severe pain in adults who require around-the-clock treatment for an extended period of time (Tramadol ER package insert, 2009).

Additional mechanism(s) of action: Inhibits the reuptake of norepinephrine and serotonin (Tramadol package insert, 2012).

Specific adverse effects

Seizures have been reported in patients receiving tramadol within the recommended dose range (Tramadol package insert, 2012).

Precautions/contraindications

  • Contraindicated with MAOIs or use within 14 days of discontinuing MAOIs (Tramadol package insert, 2012).
  • Concomitant use of tramadol with SSRIs, TCAs and other opioids increases risk of seizure (Tramadol package insert, 2012).
  • Development of serotonin syndrome has been seen when tramadol is used concomitantly with SSRIs, TCAs, MAOIs and triptans (Tramadol package insert, 2012).
  • Dose adjustments are required for immediate-release products and extended-release are contraindicated in patients with severe renal or hepatic impairment (Tramadol package insert, 2012).

Additional information

  • Available in combination with acetaminophen, or alone as a regular-release product (Tramadol package insert) and extended-release product (Tramadol ER package insert, 2009).
  • Metabolized by CYP2D6 to the active metabolite O-desmethyl tramadol, which has a higher affinity for the mu opioid receptor than the parent compound (Tramadol package insert, 2012).
  • Max daily dose is 400 mg/day (Tramadol package insert, 2012).

Tapentadol (MME = 0.4)

Indication: Tapentadol immediate-release tablets are indicated for the relief of moderate to severe acute pain in patients > 18 years of age (Nucynta package insert, 2013). Tapentadol extended release tablets are indicated for the relief of severe pain and neuropathic pain related to diabetic peripheral neuropathy (Nucynta ER package insert, 2014).

Additional mechanism(s) of action: Inhibits the reuptake of norepinephrine (Nucynta package insert, 2013).

Specific adverse effects: None

Precautions/contraindications

  • Contraindicated with MAOIs or use within 14 days of discontinuing MAOIs (Nucynta package insert, 2013).
  • Prescribe cautiously in patients with a history of seizure disorder (Nucynta package insert, 2013).
  • Development of serotonin syndrome has been seen with concomitant use of SSRIs, SNRIs, TCAs, MAOIs and triptans (Nucynta package insert, 2013).
  • Not recommended for use in patients with severe renal or hepatic impairment (Nucynta package insert, 2013).

Additional information

  • Available in regular-release (Nucynta package insert, 2013) or extended-release (Nucynta ER package insert, 2014) oral formulations.
  • Primarily metabolized by glucuronidation to inactive metabolites (Nucynta package insert, 2013).
  • Max daily dose for tapentadol is 700 mg on day one and 600 mg on subsequent days (Nucynta package insert, 2013).
  • Max daily dose for tapentadol ER is 500 mg per day (Nucynta ER package insert, 2014).
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