Papers of the Week – Classic Papers

Prognostic variables for assessing people with whiplash associated disorder (WAD) following a motor vehicle collision (MVC) have been evaluated in numerous studies. However, there is minimal evidence assessing how these variables may differ between males and females.

In an attempt to explain how and why some individuals with musculoskeletal pain develop a chronic pain syndrome, Lethem et al. (Lethem J, Slade PD, Troup JDG, Bentley G. Outline of fear-avoidance model of exaggerated pain perceptions. Behav Res Ther 1983; 21: 401-408).ntroduced a so-called 'fear-avoidance' model. The central concept of their model is fear of pain. 'Confrontation' and 'avoidance' are postulated as the two extreme responses to this fear, of which the former leads to the reduction of fear over time. The latter, however, leads to the maintenance or exacerbation of fear, possibly generating a phobic state. In the last decade, an increasing number of investigations have corroborated and refined the fear-avoidance model. The aim of this paper is to review the existing evidence for the mediating role of pain-related fear, and its immediate and long-term consequences in the initiation and maintenance of chronic pain disability. We first highlight possible precursors of pain-related fear including the role negative appraisal of internal and external stimuli, negative affectivity and anxiety sensitivity may play. Subsequently, a number of fear-related processes will be discussed including escape and avoidance behaviors resulting in poor behavioral performance, hypervigilance to internal and external illness information, muscular reactivity, and physical disuse in terms of deconditioning and guarded movement. We also review the available assessment methods for the quantification of pain-related fear and avoidance. Finally, we discuss the implications of the recent findings for the prevention and treatment of chronic musculoskeletal pain. Although there are still a number of unresolved issues which merit future research attention, pain-related fear and avoidance appear to be an essential feature of the development of a chronic problem for a substantial number of patients with musculoskeletal pain.

Although many anecdotal reports indicate that marijuana and its active constituent, delta-9-tetrahydrocannabinol (delta-9-THC), may reduce pain sensation, studies of humans have produced inconsistent results. In animal studies, the apparent pain-suppressing effects of delta-9-THC and other cannabinoid drugs are confounded by motor deficits. Here we show that a brainstem circuit that contributes to the pain-suppressing effects of morphine is also required for the analgesic effects of cannabinoids. Inactivation of the rostral ventromedial medulla (RVM) prevents the analgesia but not the motor deficits produced by systemically administered cannabinoids. Furthermore, cannabinoids produce analgesia by modulating RVM neuronal activity in a manner similar to, but pharmacologically dissociable from, that of morphine. We also show that endogenous cannabinoids tonically regulate pain thresholds in part through the modulation of RVM neuronal activity. These results show that analgesia produced by cannabinoids and opioids involves similar brainstem circuitry and that cannabinoids are indeed centrally acting analgesics with a new mechanism of action.

We applied and validated a quantitative allodynia assessment technique, using a recently developed rat surgical neuropathy model wherein nocifensive behaviors are evoked by light touch to the paw. Employing von Frey hairs from 0.41 to 15.1 g, we first characterized the percent response at each stimulus intensity. A smooth log-linear relationship was observed, with a median 50% threshold at 1.97 g (95% confidence limits, 1.12-3.57 g). Subsequently, we applied a paradigm using stimulus oscillation around the response threshold, which allowed more rapid, efficient measurements. Median 50% threshold by this up-down method was 2.4 g (1.81-2.76). Correlation coefficient between the two methods was 0.91. In neuropathic rats, good intra- and inter-observer reproducibility was found for the up-down paradigm; some variability was seen in normal rats, attributable to extensive testing. Thresholds in a sizable group of neuropathic rats showed insignificant variability over 20 days. After 50 days, 61% still met strict neuropathy criteria, using survival analysis. Threshold measurement using the up-down paradigm, in combination with the neuropathic pain model, represents a powerful tool for analyzing the effects of manipulations of the neuropathic pain state.

Opiate drugs have potent analgesic and addictive properties. These drugs interact with receptors that also mediate the response to endogenous opioid peptide ligands. However, the receptors for opioids have eluded definitive molecular characterization. By transient expression in COS cells and screening with an iodinated analog of the opioid peptide enkephalin, a complementary DNA clone encoding a functional delta opioid receptor has been identified. The sequence shows homology to G protein-coupled receptors, in particular the receptors for somatostatin, angiotensin, and interleukin-8.

A random primed expression cDNA library was constructed from the RNA of NG 108-15 cells. Pools of plasmid DNA were transfected into COS cells, which were screened for their ability to bind 3H-labeled Tyr-D-Thr-Gly-Phe-Leu-Thr, a tritiated agonist for the delta-opioid receptor. A cDNA was isolated that encodes a 371-amino acid-residue protein presenting all the structural characteristics of receptors that interact with guanine nucleotide-binding proteins. Noticeable features are (i) the high hydrophobicity of the encoded protein, (ii) its low sequence similarity to both catecholamine receptors and peptide-binding receptors, although it presents the typical aspartate residue involved in catecholamine binding of the first group and the characteristic short third cytoplasmic loop of the second group. When expressed in COS cells, the receptor exhibits pharmacological properties similar to those of the native receptor: high-affinity binding sites for 3H-labeled Tyr-D-Thr-Gly-Phe-Leu-Thr (Kd = 1.4 nM), stereospecific binding sites for the – enantiomers of levorphanol and naloxone, and the selectivity profile of a delta receptor, as determined by competition experiments with a set of mu-, delta-, and kappa-opioid ligands.

The representation of pain in the cerebral cortex is less well understood than that of any other sensory system. However, with the use of magnetic resonance imaging and positron emission tomography in humans, it has now been demonstrated that painful heat causes significant activation of the contralateral anterior cingulate, secondary somatosensory, and primary somatosensory cortices. This contrasts with the predominant activation of primary somatosensory cortex caused by vibrotactile stimuli in similar experiments. Furthermore, the unilateral cingulate activation indicates that this forebrain area, thought to regulate emotions, contains an unexpectedly specific representation of pain.

The literature on the utility of cognitive coping strategies in pain control has been unclear because of 2 principal limitations: the lack of a validated classification system, and reliance on qualitative and quasi-statistical reviews. In this study, an empirically based multidimensional taxonomy was employed to categorize the variety of cognitive coping strategies into 6 major classes: external focus of attention, neutral imaginings, pleasant imaginings, dramatized coping, rhythmic cognitive activity and pain acknowledging. Meta-analytic techniques were introduced to evaluate the overall efficacy of cognitive strategies (in comparison to no-treatment controls), the relative efficacy of these strategies (how the different groups of strategies compare with one another), and the substantive efficacy of such strategies (how cognitive strategies fare against placebo/expectancy conditions). Results revealed that, in general, cognitive coping strategies are more effective in alleviating pain as compared to either no-treatment or expectancy controls. Each individual class of strategies significantly attenuates pain although the imagery methods are the most effective whereas pain acknowledging is the least effective. Positive expectancy is no better than no treatment. These findings stand in contrast with previous reviews that have not assigned prime importance to imagery or for that matter have not shown cognitive strategies to be particularly effective. Results are discussed with reference to attentional models and methodological issues.

Facial expressions contribute substantially to judgments of sufferer's pain but have not been rigorously described. We obtained a detailed description of 72 female volunteers' facial reactions to the cold pressor experience, using Ekman and Friesen's (1978a) objective, anatomically based Facial Action Coding System. In addition, we examined the impact of exposure to social models tolerant or intolerant to pain. The facial actions systematically provoked by cold pressor exposure comprised a narrowing of the eye aperture from below, raising the upper lip, pulling the lip corners, parting of the lips, or dropping the jaw, and eyes closing or frequently blinking; however, there was rich individual variation in the facial displays. The reactions were most salient at onset, indicating blends of startle, adaptive reaction, emotional expression, and pain, but they declined in vigor over time, although self-report of pain continued to mount. The relation between subjective distress and facial expression was greatest at the beginning of noxious stimulation. The social models had a potent impact on verbal report and pain tolerance but not on facial expression, indicating relative independence of components within the rich range of expressive reactions of painful experience.