Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 2009; 63:533–43

Placebo effects are observed throughout randomized clinical trials and across diverse clinical fields. Placebo analgesia causes release of endogenous opioids in dorsolateral prefrontal cortex, rostral anterior cingulate cortex, and periaqueductal gray areas of the brain, and it inhibits pain transmitting regions of the brain such as the thalamus, insula, and dorsal anterior cingulated cortex. The authors hypothesized that placebo analgesia may activate the opioidergic descending pain-control system, perhaps resulting in the inhibition of nociceptive processes at the spinal cord level.

In this randomized, double-blinded study, volunteers received either naloxone (0.15 mg/kg bolus) or saline approximately 15 min before the test phase. Patients were informed that they were being treated with either “lidocaine” or “control” cream and then they received thermal stimulation on days 1 and 2; similar procedures were followed while patients were evaluated using functional magnetic resonance imaging. Naloxone reduced both behavioral and neural placebo effects as well as placebo-induced responses in pain-modulatory cortical structures, such as rostral anterior cingulate cortex. In a brainstem-specific analysis, a similar naloxone modulation of placebo-induced responses in key structures of the descending pain control system, including the hypothalamus, periaqueductal gray, and the rostral ventromedial medulla was observed. Most importantly, naloxone abolished placebo-induced coupling between rostral anterior cingulate cortex and periaqueductal gray, which predicted both neural and behavioral placebo effects as well as activation of the rostral ventromedial medulla.


For placebo analgesia, cortical regions activate the hypothalamus, midbrain periaqueductal gray, and brainstem rostral ventromedial medulla, which signal spinal inhibitory processing of nociceptive information. This may be a pathway used by other endogenous pain modulating systems.

Suggested by: Timothy J. Brennan, Ph.D., M.D. 

No evidence for the development of acute tolerance to analgesic, respiratory depressant, and sedative opioid effects in humans. Pain 2009; 142:17–26

Although the association of chronic opioid therapy with the development of pharmacologic tolerance is well accepted, the effects of acute opioid administration are less well defined. Acute tolerance has been demonstrated in animal studies, and human trials examining intraoperative opioid administration have provided mixed results.

In this randomized, double-blinded, placebo-controlled trial, volunteers received a 3-h intravenous infusion delivering two clinically relevant doses of the μ-opioid receptor agonist, remifentanil. The blood remifentanil concentration versus  opioid effect relationship was determined before and after infusion. Tolerance was inferred if the potency of remifentanil was significantly lower after the infusion. The cold pressor test and models of electrical and heat pain were used to assess opioid analgesia. Paco2and minute ventilation and subjective sedation scores were also measured.

Neither dose of remifentanil produced detectable tolerance to any of the measured opioid effects after a 3-h infusion. Baseline ratings for heat-induced and electrically induced pain were 51 ± 12 and 42 ± 11 mm, and 47 ± 13 and 42 ± 14 mm, 30-min after stopping the infusion, respectively. Baseline and 30-min postinfusion endurance of pain induced by the cold pressor test were 28 ± 8 s and 22 ± 10 s. There were weak but significant associations between blood remifentanil concentration and the magnitude of euphoria and pruritus. No significant association between drug concentration and nausea was detected.


Acute tolerance to potent opioids such as fentanyl and remifentanil is a controversial subject. Concerns arise about the intraoperative use of high doses of these drugs because acute tolerance may blunt opioid analgesia for postoperative pain. The authors could not detect acute tolerance to 3-h remifentanil infusions equivalent to approximately 0.13 μg · kg−1· min−1. Acute tolerance to remifentanil in the dosages used in this study is not evident.

Suggested by: Timothy J. Brennan, Ph.D., M.D. 

Nortriptyline and gabapentin, alone and in combination for neuropathic pain: A double-blind, randomized controlled crossover trial. Lancet 2009; 374:1252–61

Two to 3% of the general population is affected by neuropathic pain, resulting in impaired quality of life and daily activities. The maximum tolerated dose of many currently approved agents, when administered as monotherapy, provide relief in 40 to 60% of patients and often do not offer complete pain relief. Previous studies have demonstrated the potential of combination therapy for pain treatment.

The efficacy and tolerability of combined nortriptyline and gabapentin compared with each drug given alone was examined in this blinded, crossover trial of patients with diabetic polyneuropathy or postherpetic neuralgia, who had a daily pain score of at least 4 (scale 0–10). Patients (N = 56) were randomized to receive one of the three sequences of daily oral gabapentin, nortriptyline, and in combination. During each 6-week treatment period, drug doses were titrated and mean daily pain scores were recorded.

Seventy-one percent of enrolled patients had diabetic polyneuropathy and 29% had postherpetic neuralgia. Of the 47 patients who completed at least two treatment periods and were analyzed for the primary outcome, mean daily pain was 5.4 (95% CI, 5.0–5.8) at baseline; and at maximum tolerated dose, pain was 3.2 (2.5–3.8) for gabapentin, 2.9 (2.4–3.4) for nortriptyline, and 2.3 (1.8–2.8) for combination treatment. Pain with combination treatment was significantly lower than with gabapentin (−0.9, P = 0.001) or nortriptyline alone (−0.6, P = 0.02) in the overall population as well as when analyzed by disease. At maximum tolerated dose, the most common adverse event was dry mouth, which was significantly less frequent in patients on gabapentin than on nortriptyline or combination treatment. No serious adverse events were noted.


Treatment of neuropathic pain remains a significant problem for pain medicine specialists. Frequently, drugs used to treat neuropathic pain are combined; however, evidence for treatment using drug combinations is limited. This study supports combining gabapentin and nortriptyline for patients who respond to either drug for additional relief of neuropathic pain.

Suggested by: Timothy J. Brennan, Ph.D., M.D.