Opioid Tolerance And Opioidinduced Hyperalgesia

OT is a state of reduced opioid potency, reflecting down-regulation or desensitization of opioid-dependent, anti-nociceptive systems in the CNS. In contrast, OIH is a neuroadaptive state where opioid administration is associated with an increased response to painful stimuli (hyperalgesia), due to up-regulation or increased sensiti-zation of pronociceptive systems. These changes are reflected in a rightwards shift of the opioid dose-response curve in OT, in contrast to a downwards shift in OIH. Tolerance to opioid side effects, such as respiratory depression and nausea, may develop at different rates to analgesic tolerance. Differentiation of OT and OIH requires quantitative sensory testing and is difficult in the clinical setting.120[I]

Both OT and OIH result in dose escalation in order to maintain analgesia and most likely share similar neurobiological mechanisms; however, technically and experimentally, they are different neuroadaptive states (see Table 16.1). Mechanisms include those associated with the development of central sensitization, such as opioid receptor changes, increased NMDA receptor-channel effects, changes in the neurochemistry and genetics of higher-order nociceptors (e.g. dorsal horn), the production of pronociceptive substances such as dynorphin or nitric oxide, modulation of descending inhibitory and excitatory pathways, and the effects of pronociceptive opioid metabolites (e.g. M3G).

Behavioral conditioning may produce an association between a painful stimulus and the effects of opioid therapy (e.g. euphoria, dysphoria) administered at the same time, resulting in an opioid nocebo effect which is expressed as apparent tolerance. Opioid responsiveness may also be modified by environmental cues. For example, an addict may exhibit a marked reduction in OT while in hospital, where opioid use is no longer associated with the cues of drug-seeking in the community. Reduced opioid efficacy due to behavioral conditioning or nocebo effects is known as associative tolerance (hyperalgesia).119,120[I]

There may also be neuropsychological mechanisms for the development of apparent OT/OIH. For example, opioid-induced suppression of the hypothalamo-pitui-tary axis may lower testosterone, which causes mood disturbance and, in turn, worsening pain behavior.

OT/OIH may develop within hours of starting opioid therapy, as demonstrated by increased postoperative pain and hyperalgesia following remifentanil-based anesthe-sia.121 A recent clinical experiment using cold pressor testing found that OT/OIH developed within one month of commencing oral morphine for chronic low back pain.122 It has long been recognized that former heroin addicts on long-term methadone maintenance therapy exhibit lower thresholds to cold pressor testing and are cross-tolerant to high doses of morphine.123 Some authorities suggest that the presence of pain in some way reduces the development of OT/OIH in clinical pain, compared with addiction or animal models.124 The rate of opioid dose escalation (possibly reflecting reduced OT

Table 16.1 The major features of opioid-induced hyperalgesia and opioid tolerance.

Opioid induced hyperalgesia

Opioid tolerance

Increased pain sensitivity (hyperalgesia) Up-regulation of pronociceptive systems Downwards shift of dose-analgesia curve Decreased relative analgesic potency Hyperalgesia on QST OIH persists following withdrawal Responds to NMDA antagonist Responds to opioid rotation Responds to opioid dose decrease? Possible biological benefit

Decreased analgesic potency Down-regulation of antinociceptive systems Rightwards shift of dose-analgesia curve No change in relative analgesic potency No hyperalgesia on QST OT does not persist following withdrawal Responds to NMDA antagonist Responds to opioid rotation Responds to opioid dose increase No obvious biological benefit

NMDA, W-methyl-D-aspartic acid; OIH, opioid-induced hyperalgesia; OT, opioid tolerance; QST, quantitative sensation testing.

and OIH) is lower in the elderly and in the treatment of neuropathic pain.

Although seemingly maladaptive in the clinical context, OIH may be of some evolutionary benefit. The production of endogenous opioids after an injury initially promotes analgesia, allowing the organism to escape from danger. However, the development of (endogenous) opioid-induced and injury-related hyperalgesia a few days later helps keep the damaged body part still to allow for healing and conditions the organism to avoid the circumstances of the injury in the future. Most animal models of OIH demonstrate a biphasic response (initially analgesia followed by hyperalgesia) which supports this concept. Animals that developed OIH remained vulnerable to OIH after withdrawal and with reexposure to further opioids - a form of OIH memory. There is no evolutionary reason why OT is adaptive, so it is likely that OIH is the primary neuroadaptive state.125

Cold pressor testing is the most sensitive method of determining OIH and OT; a comparative experimental trial found no difference between opioid-treated chronic pain patients and normal controls in responses to mechanical stimuli (mechanical allodynia) or heat hyperalgesia. However, numerous clinical and experimental studies have validated cold pressor testing for detecting OT/OIH in patients on long-term opioid therapy.123,126

Clinically speaking, all patients on chronic opioid therapy will have some degree of OIH contributing to their clinical pain. A paradox arises where a patient may actually benefit from opioid dose reduction to improve analgesia. Unfortunately, there are no studies of opioid reduction in the treatment of (presumed) OIH and no way to clearly establish which patients may benefit. Nevertheless, in some patients (particularly those on "high doses''), a slow, steady reduction in opioid dose (approximately 10 percent per month) can lead to a significant reduction over time, often with improved analgesia and without precipitating withdrawal. However, it requires a clear explanation for the patient to understand the seemingly counterintuitive prospect of reducing their opioids to improve their pain, without precipitating withdrawal!

Buprenorphine or tramadol may be associated with the development of less OT/OIH. More established treatments for presumed OT/OIH include opioid rotation (see below under Opioid rotation in chronic non-cancer pain) or the use of NMDA receptor antagonists, such as ketamine. The use of multimodal analgesia, particularly gabapentin or pregabalin or combined opioid -opioid analgesia may be useful in the prevention or treatment of OIH/OT, based on preliminary experimental data. It is interesting to speculate whether as-needed opioid dosing rather than by-the-clock administration could be associated with less OT/OIH, by reducing the constant stimulation of opioid receptors by the agonist.

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