Audun Stubhaug

Assessment of pain

UNLABELLED Valid and reliable assessment of pain is essential for both clinical trials and effective pain management. The nature of pain makes objective measurement impossible. Acute pain can be reliably assessed, both at rest (important for comfort) and during movement (important for function and risk of postoperative complications), with one-dimensional tools such as numeric rating scales or visual analogue scales. Both these are more powerful in detecting changes in pain intensity than a verbal categorical rating scale. In acute pain trials, assessment of baseline pain must ensure sufficient pain intensity for the trial to detect meaningful treatment effects. Chronic pain assessment and its impact on physical, emotional, and social functions require multidimensional qualitative tools and health-related quality of life instruments. Several disease- and patient-specific functional scales are useful, such as the Western Ontario and MacMaster Universities for osteoarthritis, and several neuropathic pain screening tools. The Initiative on METHODS Measurement, and Pain Assessment in Clinical Trials recommendations for outcome measurements of chronic pain trials are also useful for routine assessment. Cancer pain assessment is complicated by a number of other bodily and mental symptoms such as fatigue and depression, all affecting quality of life. It is noteworthy that quality of life reported by chronic pain patients can be as much affected as that of terminal cancer patients. Any assessment of pain must take into account other factors, such as cognitive impairment or dementia, and assessment tools validated in the specific patient groups being studied.

Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery

Background: Tissue injury induces central sensitization in the spinal cord dorsal horn neurons via mechanisms involving N‐methyl‐D‐aspartate (NMDA) receptors, leading to secondary hyperalgesia. Using punctuate mechanical hyperalgesia as a measure of central sensitization, we examined whether induction and maintenance of central sensitization after surgery could be prevented by a low‐dose infusion of the NMDA‐receptor antagonist ketamine.

Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo.

&NA; Pain and sensory thresholds were examined before and after intravenous administration of ketamine (0.15 mg/kg), morphine (0.075 mg/kg) or saline in 8 patients with post‐herpetic neuralgia. A randomized, double‐blind, cross‐over study design was used. Post‐herpetic neuralgia was associated with impaired sensory function, as shown by reduced tactile and warm sensation in the affected compared with the contralateral non‐affected skin area. Neither ketamine nor morphine changed significantly the thresholds for warm, cold, heat pain or tactile sensation. However, ketamine normalized abnormal heat pain sensations in 4 patients, probably due to a central effect. Ketamine, but not morphine, produced significant relief of pain. Pain evoked by non‐noxious stimulation of the skin (allodynia) was significantly inhibited by ketamine as well as by morphine. Wind‐up‐like pain (i.e., pain evoked by repeatedly pricking the affected skin area) was significantly inhibited by ketamine, but significantly aggravated by morphine. Side effects were observed in all the 8 patients after injection of ketamine and in 6 patients after injection of morphine. The present results support the hypothesis that the Symbol (NMDA) receptors are involved in the control of post‐herpetic neuralgia including allodynia and wind‐up‐like pain. The NMDA receptors also may play a role in the modulation of thermal perception. Symbol. No caption available

Continuous subcutaneous administration of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine in the treatment of post-herpetic neuralgia.

&NA; The effect of continuous subcutaneous (s.c.) infusion of ketamine on nerve injury pain was examined in patients with post‐herpetic neuralgia. Five patients that reported pain relief after acute intravenous injection of ketamine were included in this open prospective study. Ketamine was administered continuously in increasing doses using a portable infusion pump (CADD‐PLUS, Pharmacia), and the treatment period for each infusion rate (0.05, 0.075, 0.10, or 0.15 mg/kg/h) was 7 days and nights. Relief Of continuous pain, as evaluated daily by visual analogue scales, was observed at the infusion rate of 0.05 mg/kg/h, but was most marked during infusion of 0.15 mg/kg/h. All the patients reported that ketamine reduced the severity of continuous pain as well as reduced the severity and number of attacks of spontaneous pain. Changes in evoked pain (allodynia and wind‐up‐like pain) were recorded before change of infusion rate. Allodynia was maximally reduced 59–100% after 1 week infusion of 0.05 mg/kg/h, and wind‐up‐like pain was maximally reduced 60–100% after 1 week infusion of 0.15 mg/kg/h. Itching and painful indurations at the injection site was the most bothersome side‐effect and for this reason 1 patient discontinued treatment after 2 weeks. Other common side‐effects were nausea, fatigue and dizziness. The present results show that continuous, spontaneous and evoked pain in patients with post‐herpetic neuralgia is reduced by continuous s.c. infusion of ketamine, but is associated with intolerable side effects.

Central Dysesthesia Pain after Traumatic Spinal Cord Injury Is Dependent on N-Methyl-D-aspartate Receptor Activation

The role of central N-methyl-D-aspartate (NMDA) receptors in the pathogenesis of central pain was examined in nine patients with central dysesthesia pain after spinal cord injury. The central pain syndrome included spontaneous continuous and intermittent pain as well as evoked pain. Pain was evoked by non-noxious stimulation of the skin (allodynia) and by repeated pricking of the skin (wind-up-like pain). The severity of continuous and evoked pain was examined before and after the intravenous infusion of either the NMDA receptor antagonist ketamine (6 micrograms/kg/min after a bolus dose of 60 micrograms/kg), the mu-opioid receptor agonist alfentanil (0.6 microgram/kg/min after after a bolus dose of 7 micrograms/kg), or placebo (0.9% NaCl). A randomized, double-blind, crossover study design was used. It was found that both continuous and evoked pain were markedly reduced by the blockade of NMDA receptors by ketamine as well as by the activation of mu-opioid receptors by alfentanil. Neither ketamine nor alfentanil significantly changed thresholds for the sensation of heat pain. The reduction of pain was not associated with severe side effects; the most severe side effect of ketamine was bothersome dizziness in one patient, and only modest side effects were caused by alfentanil. The present data provide clinical evidence that the development of central dysesthesia pain after traumatic spinal cord injury is dependent on the activation of central NMDA receptors. The results further indicate that mu-opioid receptors are involved in the control of this type of pain.

Individual differences in pain sensitivity: Genetic and environmental contributions

&NA; Large individual differences in pain sensitivity present a challenge for medical diagnosis and may be of importance for the development of chronic pain. Variance in pain sensitivity is partially mediated by genetic factors, but the extent of this contribution is uncertain. We examined cold‐pressor pain and contact heat pain in 53 identical (MZ) and 39 fraternal (DZ) twin pairs, and 4 single twins to determine the heritability of the two phenotypes, and the extent to which the same genetic and environmental factors affect both pain modalities. An estimated 60% of the variance in cold‐pressor pain and 26% of the variance in heat pain was genetically mediated. Genetic and environmental factors were only moderately correlated across pain modalities. Genetic factors common to both modalities explained 7% of the variance in cold‐pressor and 3% of the variance in heat pain. Environmental factors common to both modalities explained 5% of variance in cold‐pressor and 8% of the variance in heat pain. The remaining variance was due to factors that were specific to each pain modality. These findings demonstrate that cold‐pressor pain and contact heat pain are mainly distinct phenomena from both a genetic and an environmental standpoint. This may partly explain disparate results in genetic association studies and argues for caution in generalizing genetic findings from one pain modality to another. It also indicates that differences in pain scale usage account for a minor portion of the variance, providing strong support for the validity of subjective pain ratings as measures of experienced pain.

Cold allodynia and hyperalgesia in neuropathic pain: the effect of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine--a double-blind, cross-over comparison with alfentanil and placebo.

&NA; Cold allodynia and hyperalgesia are frequent clinical findings in patients with neuropathic pain. While there have been several clinical studies showing the involvement of central sensitization mechanisms and N‐methyl‐d‐aspartate (NMDA) receptor activation in mechanical allodynia/hyperalgesia and ongoing pain, the mechanisms of thermal allodynia and hyperalgesia have received less attention. The aim of the present study was to examine the effect of the NMDA‐receptor antagonist ketamine on thermal allodynia/hyperalgesia, ongoing pain and mechanical allodynia/hyperalgesia in patients with neuropathic pain (11 patients with post‐traumatic neuralgia and one patient with post‐herpetic neuralgia). All the patients were known to suffer from severe cold allodynia (cold pain detection threshold (CPDT): 23.8°C, median value). The &mgr;‐opioid agonist alfentanil was used as an active control. The study design was double‐blind and placebo‐controlled and the drugs were administered i.v. (bolus dose and infusion). CPDT in the asymptomatic contralateral area was found to be significantly decreased (cold allodynia) compared to CPDT in site‐ and age‐matched normal controls. Heat pain detection thresholds were found to be normal and no consistent heat hyperalgesia occurred. Alfentanil significantly reduced cold allodynia (by increasing CPDT) in symptomatic area (P=0.0076). Ketamine did not significantly increase the threshold. Significant and marked reductions of hyperalgesia to cold (visual analogue score at threshold value) were seen following both alfentanil (4.5 before, 1.4 after, median value) and ketamine (6.8 before, 0.4 after, median value). Alfentanil and ketamine also significantly reduced ongoing pain and mechanical hyperalgesia. It is concluded that NMDA‐receptor mediated central sensitization is involved in cold hyperalgesia, but since CPDT remained unaltered, it is likely that other mechanisms are present.

Persistent postsurgical pain in a general population: prevalence and predictors in the Tromsø study.

TOC summary Persistent pain after surgery is common, but prevalence of clinically relevant pain may be overestimated. Sensory abnormalities are associated with pain and more intense pain. ABSTRACT Population‐based data on the prevalence of persistent postsurgical pain are scarce. This study aimed to assess the prevalence of persistent postsurgical pain in a general population and to describe associated physical, social, and psychological factors, including symptoms of nerve injury and sensitization. A cross‐sectional survey was performed in northern Norway with questionnaire items covering surgery, pain, and sensory abnormalities in the area of surgery. Of the 12,982 participants, 24.0% (3111) had undergone one or more surgical procedures during the 3 years preceding the survey. Of these, 2043 had the surgery performed more than 3 months before the investigation. Persistent pain in the area of surgery was reported by 40.4% of the patients (826 of 2043), moderate or severe pain by 18.3% (373 of 2043). Hypoesthesia, hyperesthesia, or both was reported by 24.5% (501 of 2043). There were strong associations between sensory abnormalities and persistent pain, increasingly with higher pain intensities; odds ratios were 2.68 for hypoesthesia and 6.27 for hyperesthesia. Of the 826 individuals reporting persistent pain in the anatomical area of surgery, 51.0% reported chronic pain when questioned without specific reference to the surgery. The present study supports evidence from clinical studies of persistent postsurgical pain, indicating a high prevalence, but reveals large discrepancies in report of pain, depending on the questions asked and the context in which the questions are presented. Strong associations between sensory abnormalities and pain indicate neuropathic mechanisms in a major proportion of cases.

Continuous Invasive Blood Pressure and Cardiac Output Monitoring during Cesarean Delivery A Randomized, Double-blind Comparison of Low-dose versus High-dose Spinal Anesthesia with Intravenous Phenylephrine or Placebo Infusion

Background: Prevention of hemodynamic instability during cesarean delivery during spinal anesthesia has been the aim of several studies. Noninvasive monitoring has been used in all previous studies. This is the first study in healthy pregnant women with continuous invasive recording of arterial blood pressure, cardiac output, and systemic vascular resistance. The aim of this randomized trial was to compare the effects of two different intrathecal doses of bupivacaine, with or without intravenous phenylephrine infusion, on cardiac output and systolic blood pressure. Methods: In this double-blinded study, 80 healthy women scheduled to undergo elective cesarean delivery were randomly assigned to one of four different groups receiving 7 mg spinal bupivacaine with or without a concomitant low-dose infusion of phenylephrine (0.25 &mgr;g · kg−1 · min−1) or 10 mg spinal bupivacaine with or without phenylephrine infusion. All patients had 4 &mgr;g sufentanil added to the spinal solution and had cohydration with 750 ml saline, 0.9%. Results: The low-dose spinal bupivacaine group with intravenous phenylephrine infusion was the most stable group regarding all hemodynamic variables. The authors found significant differences between this group and the group that was given the high dose of bupivacaine with intravenous placebo infusion regarding cardiac output (P = 0.005), systemic vascular resistance (P < 0.0001), and systolic blood pressure (P = 0.012). Conclusions: This study shows that low-dose bupivacaine (with sufentanil), combined with a low-dose infusion of phenylephrine and moderate cohydration, gives the best hemodynamic stability during spinal anesthesia for cesarean delivery.

Local treatment with the N-methyl-D-aspartate receptor antagonist ketamine, inhibit development of secondary hyperalgesia in man by a peripheral action.

Due to the recent discovery of peripheral N-methyl-D-aspartate (NMDA) (and other glutamate) receptors in animal studies, the NMDA receptor antagonist, ketamine (0.83 mg/ml, 6 ml) or saline was injected s.c. preinjury in 10 healthy volunteers, to study the effect on burn-induced primary and secondary hyperalgesia. On the saline treated leg, all subjects developed primary hyperalgesia and secondary hyperalgesia. On the contralateral leg treated with ketamine, there was a significant reduction of primary hyperalgesia and an inhibition of development of secondary hyperalgesia. In an experimental day 2, lidocaine temporarily blocked the development of primary and secondary hyperalgesia. When saline was injected in the contralateral leg treated with ketamine 1 week previously (n = 6), no zone of secondary hyperalgesia was developed. In contrast, subjects (n = 3) treated with ketamine 2 weeks before, reported development of secondary hyperalgesia following saline, a preliminary indication of a long-lasting peripheral action of ketamine.