Naltrexone and problems in pain management

Injection of illicit drugs (mostly opiates) is a widespread medical and social problem throughout the developed world. Among the newer pharmacological approaches to managing addiction is the use of naltrexone as a pure opioid antagonist. In suitable patients it has several advantages over other drugs to manage addiction, but since it blocks the effects of opioids it also brings with it a clinical problem: how to manage acute pain in a patient taking naltrexone.

Naltrexone is an opioid antagonist derived by the substitution of the N-methyl group of oxymorphone. Its structure is similar to that of naloxone but it has a higher oral efficacy and a longer duration of action.¹ A single oral dose reaches peak plasma concentration in 1-2 hours with an apparent half life of about 14 hours. It is a pure antagonist at the opioid μ receptor with no intrinsic agonist effects and will totally block the effects of substantial doses of opioid analgesics. Veberey, using 25 mg intravenous heroin challenges in former drug addicts, described its effect: a 100 mg dose of naltrexone provided 96% blockade at 24 hours, 86.5% at 48 hours, and 46.6% at 72 hours.² Naltrexone seems to block all types of opioid receptors, and discontinuation produces very few signs and symptoms. However, long term use increases the concentration of opioid receptors in the brain and produces a temporary exaggeration of responses to the subsequent administration of opioid agonists.³

Oral naltrexone is licensed in the UK to promote abstinence from opioid drug abuse by completely blocking the “high” associated with these drugs. This approach is different from that of other methods of managing addictions, such as methadone (which prevents withdrawal) or disulfiram (which produces toxic metabolites). It has also been used as part of a “rapid detox” programme in which acute withdrawal is induced with naltrexone, often under general anaesthesia. In the US the Food and Drug Administration has approved its use for managing alcoholism: it reduces the incidence of relapse by reducing the euphoria and other positive reinforcing effects of ethanol use.⁴,⁵

Patient selection is important in preventing relapse while using naltrexone. Its lack of agonist activity does not provide any drug reinforcement and produces no withdrawal symptoms, and these factors are thought to account for high relapse rates. Motivation for abstinence is essential, and the highest success rates have been reported among patients from professional backgrounds.

Naltrexone is usually administered daily or three times a week to improve compliance, aiming for a daily dose of 50 mg.⁶ Long acting implantable preparations of naltrexone are available but are not licensed in the UK, though they are used in private addiction clinics. Implants are generally well tolerated and can block large amounts of heroin.

Clearly, patients receiving naltrexone will be very resistant to opioid analgesia and can pose major therapeutic challenges when they are in acute pain. All patients receiving naltrexone—particularly those whose occupation or recreation involves the risk of injury—should be told of the potential problems, and patients should routinely be warned to alert clinicians to their use of naltrexone before elective surgery. Local community drugs teams should play a part in educating patients. Pre-surgery assessment clinics should also inquire routinely about the use of naltrexone: drug users do not always match their stereotypes and their age range is wide.

Before minor or intermediate elective surgery the possibility of managing the pain with non-opioids needs to be balanced against the risk of the patient relapsing. This should involve discussion with the patient and his or her supporting community drugs team. Oral naltrexone should be discontinued 48-72 hours before the procedure. The duration of action of naltrexone after removal of an implant is unknown, and it is probably better to plan non-opioid analgesia than attempt to remove the implant.

If a patient is to undergo major surgery where severe post-operative pain is expected then again oral naltrexone should be discontinued 72 hours before-hand. A degree of resistance to opioid analgesics should be expected, although increased sensitivity is also a possibility. Whether or not to remove a naltrexone implant will need to be considered on an individual basis.

In the event of unexpected severe pain—for example, after trauma or emergency surgery—effective analgesia will depend on using non-opioids.⁷ Intravenous paracetamol is more effective than the same oral dose.⁸ High dose non-steroidal anti-inflammatory drugs, such as ibuprofen 2400 mg/day, are also effective,⁹ as is local anaesthesia (local infiltration, nerve block, or epidurals). The addition of clonidine, especially to central blocks, may improve efficacy and duration. Ketamine is an effective analgesic by virtue of its NMDA antagonism and may be useful. Tramadol is a weak opioid agonist, but there is no information on whether it would be effective.

Acute pain services should be aware of the problems with naltrexone and develop plans on how patients taking the drug should be managed both for elective admissions and in emergencies. Opioid addicts are known to have reduced thresholds to pain, and we do not know if or when thresholds return to normal after a period of abstinence. A former addict may fear that pain management will be inadequate, and stereotypical responses in healthcare staff to addicts may create a difficult environment for successful pain management. A good working relationship with the local community drugs team will help anticipate potential problems and ensure maintenance of care after patients are discharged from hospital. Failure to be aware of the potential problems of naltrexone therapy could result in the nightmare situation of a patient in severe pain who is totally unresponsive to conventional opioid therapy.