Erica Suzan

Opioid-Induced Hyperalgesia (OIH): A Real Clinical Problem or Just an Experimental Phenomenon?

Although opioid-induced hyperalgesia (OIH) is mentioned as a potential cause of opioid dose escalation without adequate analgesia, true evidence in support of this notion is relatively limited. Most studies conducted in the context of acute and experimental pain, which seemingly demonstrated evidence for OIH, actually might have measured other phenomena such as acute opioid withdrawal or tolerance. OIH studies in patients with chronic pain have used various experimental pain models (such as cold pain tolerance or heat pain intensity). Therefore, the fact that they have yielded inconsistent results is hard to interpret. Thus far, with the exception of a few clinical case reports on OIH in patients with cancer pain and one prospective study in patients with chronic neuropathic pain, evidence for OIH in patients with chronic or cancer-related pain is lacking. Whether experimental pain models are necessary for establishing the clinical diagnosis of OIH, and which specific model is preferred, are yet to be determined.

Oxycodone alters temporal summation but not conditioned pain modulation: preclinical findings and possible relations to mechanisms of opioid analgesia.

&NA; Under specific experimental conditions, oxycodone seems to exert spinal (temporal summation) rather than supraspinal (conditioned pain modulation) analgesic effects in humans. &NA; Opioid analgesia is mediated primarily by modulating (inhibiting and enhancing) pain mechanisms at the spinal and supraspinal levels. Advanced psychophysical paradigms of temporal summation (TS) and conditioned pain modulation (CPM) likely represent pain mechanisms at both levels. Therefore, the study of opioid effects on TS and CPM can shed light on their analgesic mechanisms in humans. The current randomized, double‐blind study tested the effects of oxycodone on the magnitude of both TS and CPM in 40 healthy subjects. TS was tested by measuring increments in pain intensity in response to 10 repetitive painful phasic heat stimuli. CPM was assessed by subtracting the response to a painful phasic heat stimulus administrated simultaneously with a conditioning cold pain stimulus from a painful phasic heat stimulus alone. These paradigms were tested before and at 60, 120, and 180 minutes after administration of a single oral dose of either oxycodone or an active placebo. Repeated‐measures analysis of variance revealed significant effects of oxycodone, but not placebo, on the magnitude of TS (F = 7.196, P < .001). Pairwise comparisons revealed that relative to baseline, TS was significantly reduced at 60 minutes (P = .008) and at 180 minutes (P = .017) after oxycodone administration. In contrast, no significant effects of either oxycodone (F = 0.871, P = .458) or placebo (F = 2.086, P = .106) on the magnitude of CPM were found. These results suggest that under the current experimental conditions, oxycodone exerted spinal, rather than supraspinal, analgesic effects. Furthermore, compared with CPM, TS seems more suitable for studying the mechanisms of opioid analgesia in humans.

Anti tumor necrosis factor - alpha adalimumab for complex regional pain syndrome type 1 (CRPS-I): a case series.

Evidence suggests tumor necrosis factor‐alpha (TNF‐α) mediates, at least in part, symptoms and signs in complex regional pain syndrome (CRPS). Here, we present a case series of patients with CRPS type 1, in whom the response to the anti‐TNF‐α adalimumab was assessed.

Drug Combinations in the Treatment of Neuropathic Pain

Pharmacotherapy, the main treatment option for neuropathic pain, remains a major clinical challenge. The most commonly studied drug classes in the context of neuropathic pain—antidepressants, anticonvulsants, and opioids—have only limited efficacy and frequent dose-limiting adverse effects. Yet, most guidelines recommend monotherapy as the first line of neuropathic pain treatment. Recent understanding of neuropathic pain pathophysiology suggests that multiple mechanisms, both at the peripheral and the central nervous system levels, underlie neuropathic pain, pointing to the possibility that targeting multiple mechanisms simultaneously can improve treatment outcome. A few clinical trials using various drug combinations for neuropathic pain have already been published but yielded inconsistent results, partially due to methodological problems associated with the conduction of such trials. Nonetheless, combination therapy remains an intriguing treatment option for neuropathic pain, awaiting future high-quality validating trials.

Spinal cord stimulation attenuates temporal summation in patients with neuropathic pain.

Abstract Evidence has shown that electrical stimulation at the dorsal columns attenuated the “wind-up” phenomenon in dorsal horn neurons in nerve-injured rats. This study was aimed to test the effect of spinal cord stimulation (SCS) on temporal summation (TS), the clinical correlate of the wind-up phenomenon in patients with radicular leg pain. Eighteen patients with SCS implants were tested both 30 minutes after SCS activation (“ON”) and 2 hours after turning it off (“OFF”), in a random order. Temporal summation was evaluated in the most painful site in the affected leg and in the corresponding area in the contralateral leg by applying a tonic painful heat stimulus (46.5°C; 120 seconds) and simultaneous recording of the perceived heat pain intensity. Patients were also requested to report their clinical pain intensity (0-100 numerical pain scale) during SCS “ON” and “OFF”. The Wilcoxon signed rank test was used in the comparisons between SCS “ON” and “OFF”. Spinal cord stimulation activation significantly attenuated clinical pain intensity (from 66 ± 18 to 27 ± 31, P < 0.001). In the nonpainful leg, SCS activation failed to produce an effect on TS (24 ± 20 vs 21 ± 24 in SCS “OFF” and “ON”, respectively; P = 0.277). In contrast, a significant decrease in the magnitude of TS in the affected leg was observed in response to SCS activation (from 32 ± 33 to 19 ± 24; P = 0.017). These results suggest that attenuation of TS, which likely represents suppression of hyperexcitability in spinal cord neurons, is a possible mechanism underlying SCS analgesia in patients with neuropathic pain.

Measuring the Intensity of Chronic Pain: Are the Visual Analogue Scale and the Verbal Rating Scale Interchangeable?

The 0 to 100 mm visual analogue scale (VAS) and the five‐category verbal rating scale (VRS) are commonly used for measuring pain intensity. An open question remains as to whether these scales can be used interchangeably to allow comparisons between intensities of pain in the clinical setting or increased statistical power in pain research.

The Effect of Hydromorphone Therapy on Psychophysical Measurements of the Descending Inhibitory Pain Systems in Patients with Chronic Radicular Pain

OBJECTIVE Conditioned pain modulation (CPM) and offset analgesia (OA) are considered to represent paradigms of descending inhibitory pain modulation in humans. This study tested the effects of hydromorphone therapy on descending inhibitory pain modulation, as measured by changes from baseline in the magnitudes of CPM and OA. DESIGN Prospective evaluation. SETTING Institute of Pain Medicine, Rambam Health Care Campus. SUBJECTS Patients with chronic radicular pain. METHODS Thirty patients received 4 weeks of oral hydromorphone treatment at an individually titrated dose (mean ± standard deviation dose of 11.6 ± 4.8 mg/day). CPM and OA were assessed before and after hydromorphone treatment. CPM was assessed by subtracting the response to a painful phasic heat stimulus administered simultaneously with a conditioning cold pain stimulus, from the response to the same heat stimulus administered alone. The OA paradigm consisted of a three-temperature stimuli train (T1 = 49°C [5 seconds], T2 = 50°C [5 seconds], and T3 = 49°C [20 seconds]). The magnitude of OA was quantified by subtracting minimal pain scores obtained during T3 from the maximal pain scores obtained during T2. RESULTS CPM scores changed from a baseline of 17.7 ± 20.6 to 21 ± 20.4 following treatment, and OA scores changed from 7.8 ± 20.5 to 9.7 ± 14.6. Wilcoxon signed rank test indicated that these changes were not significant (CPM: P = 0.22; OA: P = 0.44). McNemar test revealed that the percentage of patients who exhibited a change in the direction of CPM or OA in response to hydromorphone treatment was not significant (CPM: P = 0.37; OA: P = 0.48). CONCLUSIONS These results suggest that the descending inhibitory pain modulation, as manifested in humans by CPM and OA, is unlikely to be mediated by hydromorphone therapy.

Individually based measurement of temporal summation evoked by a noxious tonic heat paradigm

Background A model for measuring temporal summation (TS) by tonic noxious stimulation was recently proposed. However, methodological variations between studies make it difficult to reach a consensus regarding the way TS should be applied and calculated. The present study aimed to present a calculation method of TS magnitude produced by a tonic heat model in a large cohort of healthy subjects. Methods Noxious heat stimulation (46.5°C/2 minutes) was applied to the forearm of 154 subjects who continuously rated pain intensity using a computerized visual analog scale. TS was calculated by “mean group” and “individual” approaches. Results A “typical” pattern of pain response, characterized by a peak pain followed by a decrease in intensity to a nadir and subsequently a progressive increase in pain scores, was exhibited by 86.4% of the subjects. Using the “mean group” and “individual” calculation approaches, the mean ± standard deviation magnitudes of TS were 31.4±27.5 and 41.0±26.0, respectively (P<0.001). Additionally, using the individualized approach, we identified a different (“atypical”) response pattern among the rest of the subjects (13.6%). Conclusion The results support the tonic heat model of TS for future utilization. The individualized TS calculation method seems advantageous since it better reflects individual magnitudes of TS.

The effects of a dopamine agonist (apomorphine) on experimental and spontaneous pain in patients with chronic radicular pain: A randomized, double-blind, placebo-controlled, cross-over study

Background Although evidence suggests that dopaminergic systems are involved in pain processing, the effects of dopaminergic interventions on pain remains questionable. This randomized, double blinded, placebo-controlled, cross-over study was aimed at exploring the effect of the dopamine agonist apomorphine on experimental pain evoked by cold stimulation and on spontaneous pain in patients with lumbar radicular (neuropathic) pain. Methods Data was collected from 35 patients with chronic lumbar radiculopathy (18 men, mean age 56.2±13 years). The following parameters were evaluated before (baseline) and 30, 75 and 120 minutes subsequent to a subcutaneous injection of 1.5 mg apomorphine or placebo: cold pain threshold and tolerance in the painful site (ice pack, affected leg) and in a remote non-painful site (12°C water bath, hand), and spontaneous (affected leg) pain intensity (NPS, 0–100). Results One-hundred and twenty minutes following apomorphine (but not placebo) injection, cold pain threshold and tolerance in the hand increased significantly compared to baseline (from a median of 8.0 seconds (IQR = 5.0) to 10 seconds (IQR = 9.0), p = 0.001 and from a median of 19.5 seconds (IQR = 30.2) to 27.0 seconds (IQR = 37.5), p<0.001, respectively). In addition, apomorphine prolonged cold pain tolerance but not threshold in the painful site (from a median of 43.0 seconds (IQR = 63.0) at baseline to 51.0 seconds (IQR = 78.0) at 120 min, p = 0.02). Apomorphine demonstrated no superiority over placebo in reducing spontaneous pain intensity. Conclusion These findings are in line with previous results in healthy subjects, showing that apomorphine increases the ability to tolerate cold pain and therefore suggesting that dopaminergic interventions can have potential clinical relevance.

Methylphenidate attenuates the response to cold pain but not to aversive auditory stimuli in healthy human: a double-blind randomized controlled study

Introduction: We recently showed that the psycho-stimulant norepinephrine–dopamine reuptake inhibitor methylphenidate (MP) prolonged cold pain threshold and tolerance in adults with attention-deficit hyperactivity disorder (ADHD). Objectives: The objectives of the present study were to: (1) examine whether MP has antinociceptive properties in healthy men; (2) test MPs effects on responses to aversive auditory stimuli. The underlying aim was to determine whether MP exerts antinociceptive properties or more generalized, nonspecific attenuating effects on different aversive sensory modalities. Methods: This double-blind, crossover, randomized placebo-controlled study consisted of 2 sessions one week apart from each other. In each session, pain threshold (seconds) and tolerance (seconds) in response to painful cold stimulation were measured. Additionally, threshold (dB) and tolerance (seconds) to loud aversive auditory stimuli (500 Hz, 2000 Hz and white noise) were also tested prior to and 2 hours following the administration of a single dose of either 20 mg MP or an identical looking placebo. Results: Forty men, 26.1 ± 4.0 (mean ± SD) years were enrolled in the study. Wilcoxon signed-rank test analyses showed that MP, but not the placebo, produced a significant increase in cold pain threshold (from 4.1 ± 2.6 to 5.4 ± 3.1 seconds, P = 0.001 and from 4.5 ± 2.6 to 4.3 ± 2.7 seconds, P = 0.2, respectively) and tolerance (from 57.8 ± 54.0 to 73.8 ± 61.8 seconds, P = 0.001 and from 52.5 ± 53.7 sec to 57.0 ± 52.9 seconds, P = 0.1, respectively). No significant changes were found in any of the auditory parameters. Conclusion: These results suggest that MP has an effect on nociceptive pathways rather than a nonspecific, generalized attenuating effect on aversive sensory stimuli.