What Do We Know About Opioid-Induced Hyperalgesia?

In a prospective preliminary study of 6 patients with chronic low back pain, hyperalgesic response was detected after 1 month of oral morphine therapy using a cold pressor test but not a heat pain test [59]. In another prospective randomized, placebo-controlled, 2-way crossover study in healthy human volunteers, the development of OIH was quantified as changes in the average radius of the area of secondary hyperalgesia generated by electrical pain stimulation. A 23.6% increase in the area of secondary hyperalgesia over baseline was detected following the remifentanil infusion. The same study showed that endogenous opioids did not seem to have an effect on OIH because a single bolus of naloxone did not change the size of secondary hyperalgesia [60].

OIH Prevention Studies

Currently, efforts have also been made to see whether OIH can be prevented with different approaches in human subjects. The following is a brief summary of these studies. In a study of adolescents undergoing scoliosis surgery, treatment with morphine (150 mg/kg) prior to commencing remifentanil infusion did not prevent the development of remifentanil-induced hyperalgesia [61]. In another study, propofol infusion alone with remifentanil both delayed and attenuated remifentanil-induced hyperalgesia [53]. In yet another study, intraoperative 70% N2O administration appeared to reduce postoperative OIH following an intraoperative remifentanil-propofol anesthesia regimen [62].

In a study of 15 healthy male volunteers, preventive administration of parecoxib significantly diminished OIH after withdrawal from remifentanil. In contrast, parecoxib given together with remifentanil did not prevent OIH, suggesting that pre-treatment, not parallel treatment, with opioid may be required to prevent OIH [63]. Other NSAIDs administered preemptively also appear to prevent remifentanil-induced hyperalgesia [64].

Another study investigated the effect of intra-operative magnesium sulfate administration in patients undergoing robot-assisted laparoscopic prostatectomy. Magnesium sulfate administration reduced postoperative opioid consumption and OIH in subjects receiving intra-operative remifentanil-based anesthesia [65,66]. Intra-operative adenosine infusion also prevented acute opioid tolerance and remifentanil-induced hyperalgesia [67]. Continuous intra-operative infusion of ketamine, an NMDA receptor antagonist, significant lowered postoperative VAS and morphine use in gynecologic surgery patients [68]. Also, in a randomized, double-blind, placebo-controlled study of 90 patients who underwent total abdominal hysterectomy, cumulative morphine consumption was significantly greater in subjects with fentanyl alone than those with saline alone, ketamine alone, ketamine with fentanyl, or fentanyl with lornoxicam at 3, 6, and 12 hours postoperatively [69].

Finally, in a double-blind, randomized, placebo-controlled study of 40 patients undergoing elective shoulder surgery, clonidine was given intra-operatively in a remifentanil/propofol-based anesthesia. The results showed that clonidine did not reduce postoperative morphine consumption and pain score in these patients [70]. However, dexmedetomidine, another α2 receptor agonist, substantially reduced baseline opioid doses in hospitalized patients with OIH [71].

Quantitative Sensory Testing and OIH

Currently, diagnostic tools for OIH are still being developed. Many clinical studies have used quantitative sensory testing (QST) as a tool to assess OIH [72,73]. In a recent study, QST was used to compare pain threshold, pain tolerance, and the degree of temporal summation of pain in response to thermal stimulation among 3 groups of subjects: Group 1 (no pain and no opioid), Group 2 (chronic pain but no opioid therapy), and Group 3 (both chronic pain and opioid therapy). Group 3 subjects displayed a decreased heat pain threshold and exacerbated temporal summation of pain to thermal stimulation as compared with both group 1 and group 2 subjects. There were no differences in cold or warm sensation among all 3 groups. Among clinical factors, daily opioid dose consistently correlated with the decreased heat pain threshold and exacerbated temporal summation of second pain in group 3 subjects [72]. Another study investigated the sensitivity to cold pain and the magnitude of diffuse noxious inhibitory control (DNIC) using QST in subjects with or without opioid therapy. Pain threshold, intensity and tolerance in response to the cold pressor (1°C) were measured. They found that oral opioid use did not result in abnormal sensitivity to cold pain but altered pain modulation as detected by DNIC [74].