Analgesic tolerance without demonstrable opioid-induced hyperalgesia: a double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain.

Interest in understanding opioid-induced hyperalgesia (OIH) has increasingly grown over the last several years.  Many discussions and reviews have centered around several key issues: 1) opioids not only produce analgesia, which is their anti-nociceptive effect, but also induce hyperalgesia, which is a pro-nociceptive effect; 2) opioid tolerance itself may be part of the pro-nociceptive process; 3) the onset of OIH may be later than that of opioid tolerance and OIH may be a dose-related process (although OIH has been reported following acute and chronic opioid exposure at both high and low doses); 4) it is unclear which types of opioid and route of administration may lead to clinical presentation of OIH; and 5) although opioid tolerance, OIH, and opioid withdrawal may share some common factors and mechanisms, the mechanism underlying each of these phenomena remains unclear (1-3).

While studies of OIH have been carried out in animal models, few clinical studies have been conducted.  It is thus very encouraging that Dr. Chu’s group has conducted a prospective clinical study on both opioid tolerance and OIH in the same subjects.  Dr. Chu and his associates used a randomized, double-blinded, placebo-controlled study design with 103 subjects.   After initial survey, examination, and a series of questionnaires, the cold pressor test, heat pain test, and pain score were assessed both before and after initial remifentanyl or sham infusion.  Then, the subjects received one month of treatment with morphine or placebo (a 10 day up-titration period followed by dose maintenance up to a month with average morphine dose 78 mg/day in the morphine group).  At the end of this period, the same endpoints were assessed again following a repeat remifentanyl infusion.  The authors found that subjects in the morphine group experienced statistically significant tolerance to the analgesic effects of remifantanyl infusion as measured by cold pressor test in comparison to the placebo group.   Although subjects in the morphine group did have significant changes in their cold pressor and heat pain threshold compared to the baseline, these changes were not statistically significant from changes seen in the control group..   The authors concluded that OIH was not observed in these subjects after one month of morphine treatment in their study.   In the following sections, several issues regarding OIH are further discussed in the context of this clinical study.

First, preclinical studies have shown thatprolonged opioid exposure produces not only a loss of the opioid antinociceptive effect (opioid tolerance), a negative sign of system adaptation (desensitization), but also activation of a pronociceptive system manifested as the reduced nociceptive threshold, a positive sign of system adaptation (sensitization).   Although both opioid tolerance and OIH are initiated by opioid administration, two opposing cellular mechanisms (i.e., a desensitization process versus a sensitization process) are likely to be contributory.  In this regard, OIH is a pro-nociceptive process and can develop later than opioid tolerance.  In this study, subjects in the morphine group received one month treatment of opioid and had already shown significant changes in cold pressor and heat pain threshold (13% decrease in cold pressor test, P=0.005 and 2 % increase in heat pain test threshold, P=0.05).  Although not statistically significant in their between-group analysis, a longer duration of opioid treatment might have led to further evidence of OIH in these subjects, because OIH may well develop after prolonged opioid treatment (4,5).  

Second, dose regimen may be an important clinical factor in OIH.  In this study, the morphine dose was 78 mg /day on average.  This may be a relatively low dose in comparison with other studies in which OIH was observed in subjects on opioid therapy or opioid addicts who are on a high dose of opioid for a long period of time (6-9). Animal studies also have shown a relationship between opioid dose and the development of hyperalgesia (10). While the exact relationship between dose regimen and OIH remains to be determined, it is conceivable that OIH would be more likely to develop in patients receiving high opioid doses with a prolonged treatment course.  On the other hand, OIH has also been demonstrated in patients receiving a short course of highly potent opioid analgesics (11).

Third, the type of opioid analgesics may influence the development of OIH, an issue that was not investigated in this study.  Anecdotal clinical observations have suggested that the degree of OIH may vary according to opioid analgesics (12). There is a question of whether, if OIH develops following exposure to one opioid, switching to a different opioid can diminish OIH (13).  Moreover, patients with a pathological pain condition (e.g., neuropathic pain) treated with opioid therapy may be more susceptible to developing OIH, because both pathological pain and OIH may share a common cellular mechanism (14).

Although the results by Chu et al suggest that opioid tolerance, but not OIH, was developed in subjects taking morphine for one month at an average dose of 78 mg/day, future studies with a higher opioid dose and a longer duration of opioid treatment may provide more information regarding OIH in clinical subjects.

Understanding OIH has significant clinical implications.  In the clinical setting, apparent opioid tolerance, i.e., a decreased opioid analgesic effect during a course of opioid therapy, may result from (1) pharmacological tolerance, (2) worsening pain condition due to disease progression, (3) OIH.  Until recently, pharmacological opioid tolerance and/or a worsening clinical pain condition were often considered to be the cause of apparent opioid tolerance.   Accordingly, opioid dose escalation appeared to be a logical approach to regaining the effectiveness of opioid analgesia.   This practice may need to be reconsidered in light of OIH.  An important issue is how to distinguish elements of each differential diagnosis in the clinical setting (15). If the increased nociceptive input (e.g., disease progression) and/or psychological issues are ruled out as the primary contributor to apparent opioid tolerance, differentiating between pharmacologic tolerance and OIH should be considered.  It seems reasonable to give a trial of opioid dose escalation at this point.  If pain improves, lack of opioid analgesic efficacy (apparent opioid tolerance) is more likely due to pharmacological tolerance.  However, if pain worsens or does not respond to dose escalation, OIH could be the cause.  Clinical diagnosis of OIH also can be aided by using QST and observing various clinical features such as diffuse pain beyond the dermatome distribution of pre-existing pain.

In summary, OIH may be considered when a) prior opioid dose escalation fails to provide the expected analgesic effect and b) there is unexplainable pain exacerbation following an initial period of effective opioid analgesia.   In this regard, the goal of providing better pain control for those patients on opioid therapy may be accomplished by initiating a trial of opioid tapering, opioid rotation, adding adjunctive medications, or combining opioid with clinically available N-methyl-D-aspirate receptor antagonist.   Continuing opioid therapy with blinded dose escalations without clinical evidence of pain improvement is neither scientifically sound nor clinically justified.

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