Approximately one in five Australians suffers from chronic pain. Pain is classified as chronic when it does not subside, occurs on most days, and continues for at least three months. Many people with chronic pain find adequate relief from a specific opioid regime, whereas others can be troubled by adverse effects, tolerance and inadequate pain relief. For the latter, it has become common practice to improve treatment by changing therapy; either by formulation, route of administration, and/or opioid. Many reference sources provide opioid conversion charts to aid this process.

Webster’s recent study analysing hospital medical charts in the United States found that the class of drugs with the highest predictive value of prescribing discrepancies for adverse events was opioids. There is not sufficient data at present to conclude the reasons for the prescribing errors, however evidence suggests that the reliance on dose conversion tables may be an important contributing factor.

Most studies on opioid potency to determine equianalgesic doses are with one opioid versus a standard, usually parenteral morphine, both at a low and high dose and in patients with a minimal or relatively low opioid exposure to ensure that tolerance was unlikely. This has its drawbacks when dealing with chronic pain patients who have developed a great tolerance to their current treatment.

Tolerance is the term used to describe the effect when regular exposure to a drug over time results in a reduced effect and the need for a higher dose to maintain an adequate response. Tolerance can also occur on the first administration of a drug due to genetically determined sensitivity (or lack thereof) and this is known as innate tolerance. Acquired tolerance can be broken down into three different categories; pharmacokinetic which refers to a change in distribution of metabolism after repeated administration of the drug. Pharmacodynamic tolerance involves adaptive changes within systems affected by the drug, e.g. changes in receptor density. The third kind of acquired tolerance involves the patient using compensatory mechanisms to reduce the effect of the drug and is known as learned tolerance. This could be behavioural such as learning how to walk in a straight line while intoxicated with alcohol.

50-80% of patients with chronic pain who have responded poorly to one opioid improve after being rotated to another opioid. The terms ‘opioid switching’ and ‘opioid rotation’ are often used synonymously, however some reports clearly differentiate. ‘Opioid switching’ has been defined as occurring soon after opioid initiation due to an inadequate initial response. In this case, conversion tables can generally be used without a lot of alteration as it occurs early in treatment before tolerance has emerged. ‘Opioid rotation’ has been defined as taking place during long-term opioid treatment due to increasing adverse effects and/or reducing efficacy. In this scenario, patients may have a tolerance to their current opioid and therefore the suggested equianalgesic dose may be too high for them, therefore the dose should be adjusted.

Studies examining cross-tolerance have shown that, in animals, one drug may cause tolerance to itself only, e.g. morphine, whereas when mice were treated with methadone they were also tolerant to morphine and codeine. Evidence has shown that a mu-selective drug induces only minimal tolerance at kappa or delta receptors. Therefore this may help prescribers to choose which opioid to use first. Further studies are required to understand this cross-tolerance as results which have been shown so far are unpredictable and appear to be incomplete.

There are many other variables that these ‘general’ tables do not take into account. Organ dysfunction can cause disruption to the normal pharmacokinetics of a drug and therefore conversion is not so clear cut. For example, when switching opioids in someone with renal or hepatic impairment, the way in which both opioids are metabolised and excreted would need serious consideration. Adrenal insufficiency, hypothyroidism and abnormal plasma protein levels can also affect conversions.

Gender, race and age also play a major roll. CYP2D isoenzyme of the hepatic P450 system is known to catalyse more than 50 clinically important drugs and it is not inducible. CYP2D is involved in the metabolism of codeine, oxycodone, tramadol and many other opioids. Patients have been found to range from ultrarapid metabolisers to poor metabolisers. It has been shown that CYP2D activity is significantly greater in Caucasian than Asian patients and therefore this could explain the varying responses displayed to treatment with these opioids.

Further studies are needed to review and improve current data by analysing higher opioid doses, long-term therapy and different demographics. The importance of bidirectional change should also be considered given the above information and the scope for variation between different opioids, and to ensure the conversion table works for both drug A to drug B, and from drug B to drug A.

Switching between any two drugs, particularly between opioids, should be carried out with caution and it’s not a simple case of looking at a table and picking the relative dose. Demographics, concomitant medication, comorbidities and cross-tolerance need to be considered. From the different points raised in this article it’s clear each patient should be taken on a case-by-case basis as it could be easy to either under or over-dose them. I would suggest when using opioid conversion tables to use the lower dose of the new opioid, making sure there are adequate doses of breakthrough medication to cover the patient, and review their requirements on a daily basis.

References:

  1. Pharmaceutical Services. Chronic Pain. North Sydney: New South Wales Ministry of Health. Available from . Accessed 1 January 2013.
  2. Webster LR, Fine PG. Review and critique of opioid rotation practices and associated risks of toxicity. Pain Med 2012; 13: 562–570.
  3. Patanwala AE, Duby J, Waters J, Erstad BL. Opioid conversions in acute care. Ann Pharmacother 2007; 41: 255–66.
  4. Knotkova H, Fine PG, Portenoy RK. Opioid rotation: the science and the limitations of the euianalgesic dose table. J Pain Symptom Management 2009; 38(3): 426–39.
  5. eTG Complete. Accessed 18 April 2012. Therapeutic Guidelines Ltd (eTG35 Nov 2011).
  6. Collett B-J. Opioid tolerance: the clinical perspective. Br J Anaesth 1998; 81: 58–68.

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