Opioids for Pain
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1544
Opioids for Pain
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Med Lett Drugs Ther. 2018 Apr 9;60(1544):57-64
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Revised 5/1/18: Footnote 19 has been added to Table 2

Use of nonopioid drugs for pain was reviewed in a previous issue.1

ACUTE PAIN — For many types of moderate to severe acute pain, acetaminophen and/or an NSAID may be as effective as an opioid.2 Immediate-release formulations of full opioid agonists should generally be used for acute pain that is severe enough to require treatment with an opioid. Use of extended-release or long-acting opioid formulations initially and treatment durations >1 week have been associated with an increased risk of unintended long-term use.3,4

CHRONIC PAIN — Full opioid agonists are used for treatment of severe chronic cancer pain. Use of opioids for treatment of chronic noncancer pain is controversial; evidence of long-term effectiveness from controlled trials is limited and serious adverse effects such as overdose or opioid use disorder can occur.5,6 Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred and may be as effective as an opioid for many types of chronic pain.7 New US guidelines on prescribing opioids for chronic noncancer pain have been published (see Table 1).8,9

DOSAGE — Opioid dosage requirements vary widely from one patient to another. In general, experts recommend starting with the lowest available strength of an immediate-release opioid and titrating to effect; a reasonable starting dose is 10 mg of oral morphine per 70 kg of body weight, or its equivalent (see MME conversion factors in Table 2). The lowest dose that maintains optimum pain relief with tolerable side effects should be used; high doses have been associated with a higher incidence of overdose deaths.10 After initial titration with an immediate-release formulation and determination of the 24-hour dose requirement, an extended-release or long-acting formulation can be used in patients requiring around-the-clock dosing. In palliative care and active cancer pain treatment, rapid-onset opioids should be available for breakthrough pain.

ADVERSE EFFECTS — Sedation, dizziness, nausea, vomiting, pruritus, sweating, and constipation are the most common adverse effects of opioids; respiratory depression is the most serious. Taken in usual doses, opioids, including mixed agonist/antagonists, may decrease respiratory drive and cause apnea in opioid-naive patients, particularly those who have chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, or pre-existing respiratory depression. Tolerance to the respiratory depressant effect develops with chronic use.

Administration of naloxone can reverse severe respiratory depression resulting from an opioid overdose. Naloxone has a short half-life and repeated dosing may be needed, especially for overdose with a long-acting or extended-release opioid agonist.

Persistent opioid-induced sedation that limits activity can be ameliorated by giving small oral doses of stimulants such as methylphenidate (Ritalin, and others) in the morning and early afternoon. Modafinil (Provigil, and generics) has been shown (off label) to be beneficial in patients with opioid-induced sedation.11

Tolerance usually develops rapidly to the sedative and emetic effects of opioids, but not to constipation; a stimulant or osmotic laxative with or without a stool softener should be started early in treatment. Three peripherally-acting mu-opioid receptor antagonists, methylnaltrexone (Relistor), naloxegol (Movantik), and naldemedine (Symproic), are FDA-approved for treatment of opioid-induced constipation. They appear to be similar in efficacy and safety, but no direct comparisons are available.12-14 Lubiprostone (Amitiza), an oral chloride channel activator, appears to be less effective. Transdermal fentanyl may cause less constipation than sustained-release oral morphine.15

Opioid-induced hyperalgesia has been reported in some patients treated with high doses of opioids. These patients experience worsening pain that cannot be overcome simply by increasing the dose (as is the case in tolerance), but rather only by reducing the dose, completely discontinuing the opioid, or switching to another opioid.16

Chronic use of opioids can increase prolactin levels and reduce levels of sex hormones, resulting in reduced sexual function, decreased libido, infertility, mood disturbances, and bone loss.17 Cases of adrenal insufficiency have been reported, particularly after >1 month of opioid use.18

TOLERANCE — Tolerance develops with chronic use of opioids; the patient first notices a reduction in adverse effects and a shorter duration of analgesia, followed by a decrease in the effectiveness of each dose. Tolerance to most of the adverse effects of opioids (except constipation) develops at least as rapidly as tolerance to the analgesic effect; it can usually be surmounted and adequate analgesia restored by increasing the dose or switching to a different opioid. Cross-tolerance exists among all full agonists, but is not complete; when switching to another opioid, reducing the calculated equianalgesic dose by at least 25-50% is recommended (see MME conversion factors in Table 2). Switching opioid-tolerant patients to methadone may improve pain relief, but should be done cautiously; the equianalgesic dose of methadone is not well-established in opioid-tolerant patients.

PHYSICAL DEPENDENCE — Clinically significant dependence can develop after several days to weeks of continued treatment with an opioid. Withdrawal symptoms will occur if the drug is discontinued suddenly or an opioid antagonist or partial agonist is given. Opioids should be tapered to reduce withdrawal symptoms.

DRUG INTERACTIONS — Use of opioids with alcohol, general anesthetics, phenothiazines, sedative-hypnotics such as benzodiazepines or barbiturates, tricyclic antidepressants, or other CNS depressants increases the risk of respiratory depression and death.19 Urinary retention and severe constipation, possibly leading to paralytic ileus, could occur with concurrent use of an opioid and an anticholinergic drug. Use of opioids with serotonergic drugs has resulted in serotonin syndrome; cases have been reported more frequently with fentanyl, meperidine, methadone, tapentadol, and tramadol.18 Use of an opioid with or within 14 days of an MAO inhibitor may result in serotonin syndrome or opioid toxicity and is not recommended.

Buprenorphine, fentanyl, hydrocodone, meperidine, methadone, oxycodone, and tramadol are metabolized by CYP3A4. Concurrent administration of a drug that inhibits CYP3A4 (or discontinuation of a CYP3A4 inducer) can increase serum concentrations of these drugs and the risk of sedation and respiratory depression. Concurrent use of a drug that induces CYP3A4 (or discontinuation of a CYP3A4 inhibitor) could decrease their serum concentrations and analgesic effect, possibly leading to withdrawal symptoms. Concomitant use of methadone with CYP2B6, 2C19, 2C9, or 2D6 inhibitors (or discontinuation of inducers of these enzymes) may increase methadone plasma concentrations.20

Patients taking codeine or tramadol who are concurrently taking drugs that inhibit CYP2D6 may not experience an analgesic effect.

Concomitant use with cimetidine could potentiate the effects of morphine. Coadministration of P-glycoprotein inhibitors such as amiodarone can increase morphine exposure by about two-fold.20

PREGNANCY — Opioid use during pregnancy has been associated with preterm delivery, poor fetal growth, stillbirth, and birth defects, including neural tube defects, congenital heart defects, and gastroschisis.21 It can also lead to neonatal opioid withdrawal syndrome. Opioid withdrawal during pregnancy has been associated with spontaneous abortion and premature labor. Pregnant women who are physically dependent on opioids should receive opioid agonist maintenance therapy with buprenorphine or methadone. Neonatal toxicity and death have been reported in breastfed infants whose mothers were taking codeine.8

FULL OPIOID AGONISTS

CODEINE — Codeine is an oral opioid agonist with a long history of use as an analgesic and cough suppressant. It is a prodrug that is converted to morphine by CYP2D6. Patients who are CYP2D6 poor metabolizers (up to 10% of the population) or are taking drugs that inhibit CYP2D6, such as fluoxetine, may not be able to convert codeine to morphine and may not experience an analgesic effect. Patients who are CYP2D6 ultra-rapid metabolizers rapidly convert codeine to higher-than-usual levels of morphine, which may result in toxicity.

The FDA has issued warnings about the use of codeine in children due to concerns about the risk of respiratory depression and death. It is contraindicated for use in children <12 years old and in those <18 years old following tonsillectomy or adenoidectomy. It should be avoided in children 12-18 years old who are obese or have an increased risk of serious breathing problems and in breastfeeding women.22

FENTANYL — Fentanyl is available in parenteral, transdermal, intranasal, and oral transmucosal formulations. It is FDA-approved only for use in opioid-tolerant patients. Fentanyl should be started only after initial titration with a short-acting opioid.

Patients should be warned that exposing a fentanyl patch to heat from an external source (e.g., a heating pad), increased exertion, or high fever could increase release of the drug and the risk of respiratory depression.23 Deaths have occurred in children following accidental exposure to the patch. The FDA recommends disposing of the patch by folding the sticky sides together and flushing it down the toilet.24

HYDROCODONE — Hydrocodone is a semi-synthetic opioid that is partly metabolized by CYP2D6 to hydromorphone after oral administration. Immediate-release formulations have been available for many years in combination with acetaminophen or ibuprofen. These combinations are the most abused opioids in the US. Extended-release, single-entity, oral formulations of hydrocodone (Zohydro ER, Hysingla ER) are available for management of severe pain; they permit higher dosing than the immediate-release combination formulations.25,26

Coadministration of 40% alcohol with Zohydro ER resulted in a 2.4-fold increase in peak concentrations of hydrocodone; patients taking Zohydro ER should not consume alcoholic beverages or other products that contain alcohol.

The FDA has approved an oral, immediate-release, fixed-dose combination of benzhydrocodone, a prodrug of hydrocodone, and acetaminophen (Apadaz) for short-term (<14 days) management of acute pain severe enough to require an opioid analgesic and for which alternative treatment options are inadequate. The combination is available as tablets containing benzhydrocodone 6.12 mg/acetaminophen 325 mg that are equivalent to immediate-release hydrocodone 7.5 mg/acetaminophen 325 mg formulations. Abuse-deterrence studies were done, but did not show that the new combination is less likely to be abused by the oral or intranasal route than hydrocodone/acetaminophen combinations.

HYDROMORPHONE — A semi-synthetic opioid and a metabolite of hydrocodone, hydromorphone is available in parenteral, rectal, and immediate- and extended-release oral formulations.27 In an open-label study in patients with chronic noncancer pain, once-daily hydromorphone was similar in efficacy to twice-daily oxycodone and caused less somnolence.28 Starting dosages should be reduced in patients with moderate to severe renal impairment.

LEVORPHANOL — Oral levorphanol is used to treat chronic pain. It has a long half-life (16-18 hours) and can accumulate with repeated dosing. Levorphanol exhibits incomplete cross-tolerance when converting from other opioids and requires careful dose titration.

MEPERIDINE — Meperidine should only be used for short-term (24-48 hours) treatment of moderate to severe acute pain. It has a more rapid onset of action than morphine, but is shorter acting. Meperidine has poor oral bioavailability, is highly irritating to tissues when given subcutaneously, and can cause muscle fibrosis when given intramuscularly.

Repeated doses of meperidine can lead to accumulation of normeperidine, a toxic metabolite with a 15- to 30-hour half-life. Normeperidine can cause dysphoria, irritability, tremor, myoclonus, and, occasionally, seizures, particularly with postoperative patient-controlled analgesia, or in elderly patients or those with impaired renal function.

In patients who are taking or have recently stopped taking an MAO inhibitor, use of meperidine can cause severe encephalopathy and death.

METHADONE — Methadone is available parenterally and orally for treatment of chronic pain, and orally for maintenance treatment of opioid use disorder. In one study, methadone was similar in efficacy to long-acting morphine for first-line treatment of cancer pain.29 The plasma half-life of methadone is variable (can be as long as 5 days) and does not correlate with the duration of analgesia; close monitoring is required during the titration period because repeated doses can lead to accumulation, CNS depression, and death. In comparison to other opioids, use of methadone for pain relief has been associated with a higher risk of death from overdose.30

In addition to being a mu-agonist, methadone is also an NMDA (N-methyl-D-aspartate) receptor antagonist. NMDA receptor antagonism can be helpful when patients do not respond to other opioids, particularly when the pain has a neuropathic component. Methadone is not fully cross-tolerant with other opioid agonists. Switching from another opioid agonist to methadone should be done cautiously; the equianalgesic dose of methadone is not well established in opioid-tolerant patients.

Methadone has no active metabolites, which may be advantageous in patients with renal impairment. Dose-related QT interval prolongation, torsades de pointes, and death have been reported.31

MORPHINE — Morphine is available orally and parenterally. Given orally, morphine is well absorbed but undergoes extensive first-pass metabolism, resulting in a bioavailability of about 35%. Morphine should be used with caution in patients with severe renal impairment because accumulation of its metabolites can occur; increased concentrations of morphine-3-glucuronide, a neurotoxic metabolite, may cause agitation, confusion, delirium, and other adverse effects.

OXYCODONE — Oxycodone, a semi-synthetic opioid, is only available orally in the US. It is frequently used in combination with acetaminophen for treatment of acute pain. A long-acting formulation is commonly used for treatment of chronic cancer pain.

OXYMORPHONE — A metabolite of oxycodone, oxymorphone is available in parenteral and in immediate- and extended-release oral formulations.32 Opana ER, an oral extended-release formulation of oxymorphone, has been removed from the market due to a high risk of serious adverse events when abused by injection; generic formulations of oral extendedrelease oxymorphone remain in production.

ABUSE-DETERRENT OPIOIDS — Several full-agonist opioids are available in abuse-deterrent formulations, both alone and in combination with opioid antagonists; there are no generic equivalents to these products (see Table 2). These formulations have one or more properties that make their intentional nontherapeutic use more difficult, less attractive, or less rewarding. No studies comparing the relative safety of these products are available. Whether using abuse-deterrent opioid products actually reduces overall opioid abuse remains to be determined. No opioid formulation prevents consumption of a large number of intact dosage units, the most common method of abuse.33-35

FULL AGONIST/REUPTAKE INHIBITORS

TAPENTADOL — Tapentadol is an oral opioid agonist and a norepinephrine reuptake inhibitor.36 It is a schedule II controlled substance and is available in immediate- and extended-release formulations. The extended-release formulation appears to provide analgesic efficacy similar to that of extended-release oxycodone with fewer adverse GI effects.37 Due to its serotonergic effects, it is contraindicated for use with or within 14 days of taking an MAO inhibitor.

TRAMADOL — An oral centrally-acting opioid agonist that weakly inhibits reuptake of norepinephrine and serotonin, tramadol is used to treat moderate to moderately severe pain. It is available alone and in combination with acetaminophen (Ultracet, and generics); the effectiveness of the combination for treatment of chronic pain is comparable to that of combinations of acetaminophen with codeine or oxycodone. The need for slow dose titration to decrease nausea and improve tolerability when initiating tramadol limits its use for treatment of acute pain. Tramadol may also be effective for treatment of neuropathic pain, but the supporting evidence is weak.38

Seizures have been reported with tramadol; patients with a history of seizures and those concomitantly taking a tricyclic antidepressant, a selective serotonin reuptake inhibitor, an MAO inhibitor, other opioids, or an antipsychotic drug may be at increased risk. Administration of naloxone for an overdose of tramadol may increase seizure risk. Tramadol is metabolized by CYP2D6 to a metabolite that is more active than tramadol itself; CYP2D6 poor metabolizers or those taking CYP2D6 inhibitors may not experience an analgesic effect. Concentrations of the active metabolite of tramadol may be higher in CYP2D6 ultra-rapid metabolizers, resulting in a higher incidence of adverse effects. Concurrent use of tramadol with drugs that inhibit CYP2D6 or 3A4 can increase tramadol levels and seizure risk.20

The FDA has issued warnings about cases of life-threatening respiratory depression and death that occurred in children who received tramadol. It is contraindicated for treatment of pain in children <12 years old and for treatment of pain after tonsillectomy or adenoidectomy in those <18 years old. Use of tramadol should be avoided in children 12-18 years old who are obese or have an increased risk of serious breathing problems and in breastfeeding women.22 Tramadol is classified as a schedule IV controlled substance because it can cause psychological and physical dependence.

A PARTIAL AGONIST

The partial agonist buprenorphine is available in oral transmucosal (Belbuca) and parenteral formulations (Buprenex, and generics), and in a transdermal patch (Butrans) for treatment of pain. In some studies, oral or transdermal buprenorphine was effective in reducing pain in patients with chronic back pain.39,40 Because of the low maximum dose of the patch (20 mcg/hr), it is not useful for treatment of severe cancer pain. Patients maintained on transdermal buprenorphine may require higher-than-normal doses of full opioid agonists during and for up to 48 hours following discontinuation of the patch.

Buprenorphine is also FDA-approved for maintenance treatment of opioid use disorder in oral transmucosal formulations (alone and in combination with the opioid antagonist naloxone), as a subdermal implant (Probuphine), and as a once-monthly injection (Sublocade); it is safer than methadone because it has a ceiling on its respiratory depressant effect and a lower abuse potential, and is less likely to prolong the QT interval (In high doses, buprenorphine can prolong the QT interval).5,41 Nausea, headache, dizziness, and somnolence are common adverse effects of buprenorphine.

MIXED AGONIST/ANTAGONISTS

The mixed agonist/antagonists pentazocine (Talwin), butorphanol, and nalbuphine all have a ceiling on their analgesic effects and can precipitate withdrawal symptoms in patients physically dependent on full opioid agonists. All are less likely than full agonists to cause physical dependence, but none is entirely free of dependence liability.

Comparison Table: Some Oral/Topical Opioid Analgesics

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