Variation in metabolism is linked to genetics, with the reported prevalence of ultra-rapid metabolisers ranging from 1 to 25%, depending on genetic background.3 Consequently, it is possible, albeit uncommon, to have a significant level of opioid tolerance while taking relatively low therapeutic doses of OTC codeine. For example, as few as eight tablets per day of OTC codeine has led to dependence requiring opioid agonist treatment. Similarly, opioid toxicity has been reported in patients taking relatively low daily doses of codeine. The patient’s symptoms on opioid cessation and assessment of other clinical indicators should drive the treatment approach as much as the codeine dose.
Patients who are likely to be codeine dependent
Patients who have been taking codeine regularly (at least daily and probably multiple times a day for months or years) are likely to have developed tolerance to codeine and may have developed dependence, as in the case of Ivana (Box 7). These patients may take codeine for pain or for nonpain reasons such as insomnia and to help with psychological distress.
Other characteristics commonly associated with codeine dependence include:
- difficulty stopping or inability to imagine stopping codeine use
- emergence of withdrawal symptoms six to 12 hours after the last codeine dose
- self-medication with opioids for opioid withdrawal that has been self-diagnosed as re-emergence of pain (e.g. rebound headaches)
- other substance use disorders (more often alcohol, benzodiazepines and less frequently other opioids or other illicit drugs)
- concurrent mental health conditions.
Management principle: advise patients with significant codeine dependence to consider maintenance treatment with buprenorphine–naloxone or methadone, following national guidelines.5 Another option is detoxification. Address any concurrent mental health problems and investigate for possible adverse effects of high-dose ibuprofen or paracetamol, as relevant.
Management options for codeine dependence
Maintenance treatment with buprenorphine–naloxone or methadone (also termed substitution treatment) is indicated for the treatment of opioid dependence, including codeine dependence.5 Other opioids, such as oxycodone–naloxone, are not indicated in the treatment of opioid dependence. Most state and jurisdictional regulations preclude use of opioids other than methadone and buprenorphine (with or without naloxone) for the treatment of opioid dependence.
Detoxification is an alternative to maintenance treatment, particularly for patients who have less severe dependence and no medical problems such as liver, kidney and gastrointestinal complications due to the use of high doses of ibuprofen or paracetamol in codeine-containing products or other factors that increase the risk of relapse. For patients who have used larger doses of opioids and have established opioid dependence, short-term opioid tapering is associated with poorer treatment outcomes compared with maintenance treatment with opioid agonists.6 The low rates of success for short-term withdrawal and risk of overdose with loss of tolerance should be discussed with the patient. The patient should be advised that if codeine withdrawal management is unsuccessful then maintenance treatment with supervised buprenorphine–naloxone or methadone is indicated.
Concurrent mental health problems such as anxiety should be addressed. Options include face-to-face psychological support (e.g. through a mental healthcare plan) or online support (e.g. through services such as beyondblue). During initial withdrawal, psychosocial approaches are recommended before psychotropic medications, as opioid withdrawal symptoms can contribute to diagnostic uncertainty.
When a patient is codeine dependent, longer-term prescribing of opioids should be under the framework of supervised medication-assisted treatment of opioid dependence (e.g. with buprenorphine–naloxone or methadone). Clinicians should contact the local health department to confirm requirements in their jurisdiction before prescribing pharmacotherapy, in addition to checking electronic medical records and prescription monitoring records where these are available.
When patients report taking large doses of ibuprofen plus codeine or paracetamol plus codeine combination products, relevant investigations should be considered, particularly to assess for renal and hepatic impairment and for anaemia. A range of serious and even fatal consequences have been reported with long-term high-dose use of codeine combination products, including perforated gastric ulcer, hypokalaemia and liver failure.7
Weaning off codeine in an outpatient setting
An opioid taper may be appropriate for patients who:
- show evidence of physiological dependence to codeine but no clear diagnosis of opioid dependence
- are otherwise in good health and do not have concurrent comorbidities that warrant specialist assessment or admission for inpatient treatment
- have no other concurrent substance use disorders and are not using other psychoactive substances of concern
- have home and social environments that are safe, supportive and free from other substance use.
Patients who have significant comorbidity or concurrent substance use disorder may be best managed in a specialist drug treatment setting, in an outpatient setting through a shared-care arrangement, or with the input and support of health care providers and services specialising in treatment of substance use disorders.