"Weak" opioid analgesics. Codeine, dihydrocodeine and tramadol: no less risky than morphine

Prescrire Int. 2016 Feb;25(168):45-50.


So-called weak opioid analgesics are often used to treat severe pain, or when paracetamol or a nonsteroidal anti-inflammatory drug (NSAID) proves inadequate. But are weak opioids any more effective than paracetamol or NSAIDs on nociceptive pain, and are they better tolerated than morphine? To answer these questions, we conducted a review of literature using the standard Prescrire methodology. The potency of codeine and tramadol is strongly influenced by the cytochrome P450 isoenzyme CYP2D6 genotype, which varies widely from one person to another. This explains reports of overdosing or underdosing after administration of standard doses of the two drugs. The potency of morphine and that of buprenorphine, an opioid receptor agonist-antagonist, appears to be independent of CYP2D6 activity. All "weak" opioids can have the same dose-dependent adverse effects as morphine. There is no evidence that, at equivalent analgesic efficacy, weak opioids carry a lower risk of addiction than low-dose morphine. Respiratory depression can occur in ultrarapid metabolisers after brief exposure to standard doses of codeine or tramadol. Similar cases have been reported with dihydrocodeine in patients with renal failure. In addition, tramadol can cause a serotonin syndrome, hypoglycaemia, hyponatraemia and seizures. Several trials have compared different weak opioids in patients with post-operative pain. A single dose of a weak opioid, possibly combined with paracetamol, has greater analgesic efficacy than paracetamol alone but is not more effective than an NSAID alone. There is a dearth of evidence on weak opioids in patients with chronic pain. Available trials fail to show that a weak opioid has markedly superior analgesic efficacy to paracetamol or an NSAID. Sublingual buprenorphine at analgesic doses appears less likely to cause respiratory depression, but it seems to have weak analgesic efficacy. In practice, when opioid therapy is needed, there is no evidence that codeine, dihydrocodeine or tramadol is less risky than morphine at its lowest effective dose. Compared to morphine, the efficacy of these drugs varies more from one patient to another, and their multiple pharmacokinetic interactions can be difficult to manage. There is also a sometimes unpredictable risk of serious over-dose. Tramadol has additional adverse effects unrelated to its opioid effects. Weak opioids require at least as much vigilance as morphine, despite the major differences in their reputation and regulation.

Publication types

  • Review

MeSH terms

  • Analgesics, Opioid / adverse effects*
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Chronic Pain / drug therapy
  • Codeine / adverse effects*
  • Codeine / analogs & derivatives*
  • Dose-Response Relationship, Drug
  • Humans
  • Morphine / adverse effects*
  • Respiration / drug effects
  • Tramadol / adverse effects*


  • Analgesics, Opioid
  • Anti-Inflammatory Agents, Non-Steroidal
  • Tramadol
  • Morphine
  • dihydrocodeine
  • Codeine