Over-the-Counter Codeine—from Therapeutic Use to Dependence, and the Grey Areas in Between

Cytochrome P450 (CYP) 2D6 is one of the most investigated CYPs in relation to genetic polymorphism, but accounts for only a small percentage of all hepatic CYPs (approximately 2-4%). There is a large interindividual variation in the enzyme activity of CYP2D6. The enzyme is largely non-inducible and metabolizes approximately 25% of current drugs. Typical substrates for CYP2D6 are largely lipophilic bases and include some antidepressants, antipsychotics, antiarrhythmics, antiemetics, beta-adrenoceptor antagonists (beta-blockers) and opioids. The CYP2D6 activity ranges considerably within a population and includes ultrarapid metabolizers (UMs), extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). There is a considerable variability in the CYP2D6 allele distribution among different ethnic groups, resulting in variable percentages of PMs, IMs, EMs and UMs in a given population. To date, 74 allelic variants and a series of subvariants of the CYP2D6 gene have been reported and the number of alleles is still growing. Among these are fully functional alleles, alleles with reduced function and null (non-functional) alleles, which convey a wide range of enzyme activity, from no activity to ultrarapid metabolism of substrates. As a consequence, drug adverse effects or lack of drug effect may occur if standard doses are applied. The alleles *10, *17, *36 and *41 give rise to substrate-dependent decreased activity. Null alleles of CYP2D6 do not encode a functional protein and there is no detectable residual enzymatic activity. It is clear that alleles *3, *4, *5, *6, *7, *8, *11, *12, *13, *14, *15, *16, *18, *19, *20, *21, *38, *40, *42, *44, *56 and *62 have no enzyme activity. They are responsible for the PM phenotype when present in homozygous or compound heterozygous constellations. These alleles are of clinical significance as they often cause altered drug clearance and drug response. Among the most important variants are CYP2D6*2, *3, *4, *5, *10, *17 and *41. On the other hand, the CYP2D6 gene is subject to copy number variations that are often associated with the UM phenotype. Marked decreases in drug concentrations have been observed in UMs with tramadol, venlafaxine, morphine, mirtazapine and metoprolol. The functional impact of CYP2D6 alleles may be substrate-dependent. For example, CYP2D6*17 is generally considered as an allele with reduced function, but it displays remarkable variability in its activity towards substrates such as dextromethorphan, risperidone, codeine and haloperidol. The clinical consequence of the CYP2D6 polymorphism can be either occurrence of adverse drug reactions or altered drug response. Drugs that are most affected by CYP2D6 polymorphisms are commonly those in which CYP2D6 represents a substantial metabolic pathway either in the activation to form active metabolites or clearance of the agent. For example, encainide metabolites are more potent than the parent drug and thus QRS prolongation is more apparent in EMs than in PMs. In contrast, propafenone is a more potent beta-blocker than its metabolites and the beta-blocking activity during propafenone therapy is more prominent in PMs than EMs, as the parent drug accumulates in PMs. Since flecainide is mainly eliminated through renal excretion, and both R- and S-flecainide possess equivalent potency for sodium channel inhibition, the CYP2D6 phenotype has a minor impact on the response to flecainide. Since the contribution of CYP2D6 is greater for metoprolol than for carvedilol, propranolol and timolol, a stronger gene-dose effect is seen with this beta-blocker, while such an effect is lesser or marginal in other beta-blockers. Concordant genotype-phenotype correlation provides a basis for predicting the phenotype based on genetic testing, which has the potential to achieve optimal pharmacotherapy. However, genotype testing for CYP2D6 is not routinely performed in clinical practice and there is uncertainty regarding genotype-phenotype, gene-concentration and gene-dose relationships. Further prospective studies on the clinical impact of CYP2D6-dependent metabolism of drugs are warranted in large cohorts of subjects.

The heightened interest in pain management is making the need for appropriate boundary setting within the clinician-patient relationship even more apparent. Unfortunately, it is impossible to determine before hand, with any degree of certainty, who will become problematic users of prescription medications. With this in mind, a parallel is drawn between the chronic pain management paradigm and our past experience with problems identifying the "at-risk" individuals from an infectious disease model. By recognizing the need to carefully assess all patients, in a biopsychosocial model, including past and present aberrant behaviors when they exist, and by applying careful and reasonably set limits in the clinician-patient relationship, it is possible to triage chronic pain patients into three categories according to risk. This article describes a "universal precautions" approach to the assessment and ongoing management of the chronic pain patient and offers a triage scheme for estimating risk that includes recommendations for management and referral. By taking a thorough and respectful approach to patient assessment and management within chronic pain treatment, stigma can be reduced, patient care improved, and overall risk contained.

Abuse of prescription analgesics in the USA is increasing. The epidemic has been driven by many factors, including marketing strategies, incorrect prescribing practices, a variety of legal and illegal drug sources, belated governmental responses and increases in the number of prescriptions written. Data sources including surveys, emergency room visits, treatment admissions, overdose deaths, toxicology laboratory findings and journal articles were examined to identify trends. The surveys and emergency department visits show use lowest among young teenagers and highest among older teenagers and young adults, with significant increases among those aged 55 and older. The length of time between initial use of an opioid other than heroin and admission to treatment is shortening. Mortality data and toxicology exhibits confirm the increases and show the variation in the prevalence of various drugs across the USA. Abuse is increasing, with varying patterns of use by high-risk groups and different geographic preferences. Prescription drug monitoring programs are being developed in each of the US states to deter 'doctor shopping'; the Food and Drug Administration has increased authority over manufacturers; and options for proper disposal of leftover medications exist. There is increased emphasis on responsible prescribing including risk assessments, prescribing agreements, treatment plans, and training for clinicians, as well as monitoring the interactions with benzodiazepines. However, unless these efforts decrease diversion, abuse and addiction, clinicians may lose the ability to use some of these opioids for effective pain management or so many barriers will be raised that pain will go undertreated or untreated. © 2011 Australasian Professional Society on Alcohol and other Drugs.