Cardiovascular events

Avoid coadministration of methadone and diazepam (Valium), which may potentiate the adverse cardiac effects of methadone.9

Avoid coadministration with other drugs that prolong the corrected QT interval.

Constipation and abdominal pain

With severe and chronic constipation that is unresponsive to the usual remedies, consider methylnaltrexone (Relistor), an opioid-receptor antagonist that has limited ability to cross the blood-brain barrier and can reverse opioid-induced constipation without precipitating withdrawal or increasing pain.18

Decrease or taper opioids. In one study, opioid weaning after a four- to 11-day protocol was associated with improvements in abdominal and nonabdominal pain, as well as pain scores.19

Depression

Treat with antidepressants and/or psychotherapy (but avoid tricyclics because they also have overdose risk).

Limit take-home doses and other central nervous system depressants to decrease the risk of suicide.20

Encourage use of mental health services, and monitor for aggression and impulsivity, which have been associated with an increased risk of suicide in patients with chronic pain.21

Hormonal dysregulation

Consider measuring hormone levels and using hormone replacement when indicated.

Consider buprenorphine over methadone.22

Decrease or slowly discontinue opioid therapy.23

Opioid-induced hyperalgesia24–28

Taper the dosage and see if pain improves.

During tapering, inform the patient that opioid withdrawal is associated with physical pain, and does not necessarily represent progression of the underlying disease.

Do not reassess pain until acute opioid withdrawal is complete (usually two to four weeks).

Opioid misuse and opioid use disorder (addiction)

When opioid misuse is detected, do not discharge the patient from your practice or refuse to prescribe opioids. Instead, add opioid misuse to the problem list and intervene to change the behavior: educate the patient about the risks of misuse, schedule visits at shorter intervals, prescribe smaller drug quantities without refills (e.g., a two-week rather than a four-week supply), and perform urine drug screening. If aberrant behavior resolves, reward course correction (e.g., resume original prescribing and visit pattern). If aberrant behavior continues, assess for the presence of an opioid use disorder and treat accordingly.29–34

Switch to buprenorphine/naloxone (Suboxone) to treat addiction and chronic pain. This requires special training and a license waiver, and the therapy can be initiated only when the patient is in active opioid withdrawal.

Refer to a methadone maintenance treatment clinic.

Taper opioids and prescribe naltrexone (Revia), an opioid-receptor blocker.

Refer for specialized addiction treatment.

Offer naloxone, an opioid-receptor antagonist that can reverse overdose, to patients at risk of overdose and, where allowed by state law, to individuals (Good Samaritans) who may be in a position to witness and reverse opioid overdose.35–37

Physiologic dependence and withdrawal (Table 6)

Taper opioid therapy gradually. Provide nonaddictive medications to lessen symptoms of withdrawal, including antinausea and antidiarrheal agents, muscle relaxants, and alpha-adrenergic receptor agonists (clonidine).

Suppressed breathing and overdose

Consider a sleep study to evaluate for apnea.

Avoid coprescribing with benzodiazepines and other sedatives, especially in patients with opioid misuse or opioid use disorder.10,15,35,36,38–41

Monitor for concurrent alcohol consumption, especially binge drinking, with a one-question screen: “Have you had six or more drinks on one occasion any time in the past year?” If the patient screens positive, evaluate for an alcohol use disorder, and consider lowering or discontinuing opioid therapy if the patient has signs and symptoms of an alcohol use disorder.

Advise patients to take precautions with opioids (e.g., never crush or chew long-acting opioids; never cut patches [unless advised by a physician] or expose them to heat, which may change the delivery mechanism; never use patches in any way other than applying them to the skin).

Offer naloxone to patients and, where allowed by state law, to Good Samaritans who may be in a position to witness and reverse opioid overdose.

Tolerance

Total dosages should not exceed a morphine equivalent of 120 mg per day, at which point consider referral to a pain management subspecialist.

Switch to another opioid, but beware of difficulties in doing so, because dose conversion is challenging (Table 1).

Acknowledge that because of tolerance, effective pain relief is not achievable, then taper off opioid.