[Mechanisms of opioid tolerance and opioid dependence]

Prescription of opiates to non cancer chronic pain patients is controversial, partly because of the risk of tolerance and dependence development. The two objectives of that review were: a) to identify the factors which may explain the variability of tolerance and dependence in clinical practice; b) to analyse the cellular mechanisms of occurrence of those phenomenons.

To our own file, we added articles retrieved in the Medline database, using, alone or in combination, following key-words (opiate, tolerance, dependence, opiate receptor, pain treatment, cAMP, cGMP, NO, NMDA, protein kinase, gene). Out of nearly 450 articles, we selected less than 200.

Tolerance, defined as loss of opioid efficacy with time, is extremely variable and depends on pain mechanisms, intrinsic efficacy and administration modality of the opioid, as well as co-administration of other agents. Physical dependence is a consequence of the intrinsic and extrinsic adaptations concerning structures as locus coeruleus, paragigantocellular nucleus, spinal cord. Acute and chronic application of opiates and withdrawal give rise to cellular adaptations which depend on the nature and efficacy of the opiate, the type of receptor and second messengers, as well as the type of cell line under study. These cellular mechanisms have consequences on neuronal excitability and gene expression. They constitute a model of cellular tolerance and dependence, but cannot explain the subtelties encountered in clinical practice.