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Division of Anesthesiology, Armed Forces Taoyuan General Hospital, Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
To the Editor:
Mercadante et al. (1) reported four cases that responded poorly to intrathecal morphine and bupivacaine for pain relief, and as a result they switched to morphine and lidocaine, which improved the analgesia. They concluded that this phenomenon was due to tachyphylaxis of local anesthetics. We agree partly their opinion.
Opioids may also activate the pain facilitatory system via activation of the N-methyl-D-aspartate (NMDA) receptors, which may produce hyperalgesia/allodynia (2–7) Indeed, NMDA antagonists have been demonstrated particularly effective in reducing persistent pain associated with central sensitization (8) Moreover, the central nervous system can synthesize and release neuropeptides that act via endogenous and exogenous opioid receptors to attenuate analgesic effects (9) As more opioids are given, more antiopioid peptides are released, thereby leading to attenuation of the analgesic effect of opioids.
We have managed a case of complex regional pain syndrome type 1 of left foot pain relief for 2 yr. Initially, lumbar epidural pain control with morphine and bupivacaine was prescribed. The patient obtained adequate pain relief (VAS 9 to 5) and resumed walking with a dose of 8 mg of morphine and 80 mg of bupivacaine daily. After 8 wk, a progressive decrease of analgesic effect (VAS 5 to 7) was found; thereafter, bupivacaine was substituted with lidocaine 320 mg daily. This change provided better pain relief (VAS 7 to 5) and allowed the patient to walk again for about 6 wk. Alternatively, we switched lidocaine and bupivacaine for 1 yr, if the analgesic effect was reduced. However, tolerance to morphine (8 mg to 12 mg/day) and persistent hyperalgesia/allodynia (VAS 9) were noted gradually. Subsequently, ketamine 80 mg/day was added for 2 mo. The VAS pain score was reduced from 5 to 3 and hyperalgesia/allodynia was reduced to VAS 5. Naloxone 10 µg/day was also prescribed for another 2 mo. Morphine was gradually reduced to 10 mg/day, and the hyperalgesia/allodynia was reduced to VAS 3.
In conclusion, besides tachyphylaxis of local anesthetics, the opioid-induced hyperalgesia and tolerance must be considered. From a clinical viewpoint, an appropriate medication for preventing both opioid-induced hyperalgesia and tolerance would be the concomitant use of opioid agonists (morphine), NMDA receptor antagonists (ketamine), and antiopioid antagonists (naloxone) (9).
References
Anesthesia and Intensive Care Unit and Pain Relief and Palliative Care Unit, La Maddalena, Cancer Center, Palermo, Italy
In Response:
Yang et al. raise a relevant topic in pain management, that is the complex phenomenon of tolerance and hyperalgesia associated with opioid use, either systematically or spinally administered. Clinical and experimental studies suggest that opioids, intended to abolish pain, can unexpectedly produce abnormally heightened pain sensations, which are characterized by a lowering of the pain threshold (hyperalgesia), and pain elicited by normally innocuous stimulation (allodynia) (1). Such abnormal sensations have been described as being quantitatively different from normal pain sensation and differentially localized from the site of the original pain complaint. These conditions are difficult to identify and controversies exist about the real occurrence of this phenomenon in clinical setting.
We reported patients who had several elements suggestive for such a syndrome, in which increasing pain was pursued by escalating opioid doses, which resulted in a worsening of the clinical picture. Of interest, interruption of this vicious circle by administering spinal local anesthetics was effective in minimizing hyperalgesia in two advanced cancer patients (2). Although much experimental data exist to explain these clinical changes of opioid response, no data exist on how, when, and why this occurs. This should be the challenging future question to resolve in appropriate cancer pain models.
While we do not exclude that this mechanism is operating in clinical practice, the cases presented in our paper focused on local anesthetic activity (3), considering that the improvement in analgesia was obtained without changes in intrathecal opioid doses. On the other hand, experimental work has also underlined the antihyperalgesic effect of local anesthetics, particularly lidocaine, resembling in some way ketamine at the level of the spinal cord (4).
No doubt that the use of epidural ketamine proposed by Yang et al. could be helpful in the context of opioid-induced hyperalgesia, according to the theory of a common pathway occurring for opioid-induced tolerance and hyperalgesia, associated with a state of hyperexcitation implicating NMDA-receptor activation (1). However, similar effects could potentially be obtained with systemic ketamine. The use of naloxone is even more controversial and debated in literature, despite encouraging reports and experimental data (5,6) and should be carefully assessed. More studies are needed to assess the most appropriate methods to reduce the phenomenon of hyperalgesia occurring with increasing doses of opioids.
References
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