May Haddad

Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain - new perspective of opioid-induced hyperalgesia.

Abstract Opioids can elicit unexpected changes in pain sensitivity, known as opioid‐induced hyperalgesia (OIH). The aim of this study was to explore whether OIH exists in patients with chronic pain treated with oral opioids (OP) versus non‐opioid (NOP) analgesics. The sensitivity to cold pain and the magnitude of diffuse noxious inhibitory control (DNIC) were evaluated in 73 OP and 37 NOP treated patients. Pain threshold, intensity and tolerance in response to the cold pressor (1 °C) were measured. DNIC was tested by co‐administrating conditioned heat stimulation (47 °C) to the left forearm and a conditioning stimulation of 12 °C for 30 s to the right hand. The results showed no differences between the two groups in any of the cold pain measures. In contrast, the magnitude of DNIC was significantly larger in the NOP than in the OP treated patients (p = 0.003). A gender based analysis showed a significant difference in DNIC between OP and NOP treated men only. However, a mixed model ANOVA demonstrated a significant effect of treatment (OP versus NOP) (F = 5.928, p = 0.017) rather than gender on DNIC. A regression analysis showed that opioid dosage and treatment duration had a significant negative effect on the magnitude of DNIC in OP treated men (β = −2.175, p = 0.036 and β = −2.061, p = 0.047, respectively). In conclusion, oral opioids usage for the treatment of chronic pain does not result in abnormal sensitivity to cold pain, but seems to alter pain modulation. The use of ‘advanced’ psychophysics tests such as evaluation of DNIC can help understanding the phenomenon of OIH.

Associations between polymorphisms in dopamine neurotransmitter pathway genes and pain response in healthy humans.

ABSTRACT Although evidence shows that several dopamine neurotransmission pathway genes are associated with specific clinical pain syndromes, such as fibromyalgia, chronic headache, and postoperative pain, the exact role of dopamine in pain processing is not fully understood. The aim of this study was to explore the relationship between functional polymorphisms in dopaminergic candidate genes and sensitivity to pain in healthy subjects. Healthy subjects (n = 192; 105 F, 87 M) were exposed to experimental tonic cold pain (1 °C) and phasic heat pain (47 °C) stimuli. DNA samples were obtained from both participants and their parents. The relationships between pain response (intensity in response to heat and cold; threshold and tolerance in response to cold only) and the functional Variable Number of Tandem Repeat (VNTR) polymorphisms of three dopamine‐related genes were investigated using a Transmission Disequilibrium Test (TDT). Specifically, 30‐bp repeat in the promoter region of the monoamine oxidase‐A gene (MAO‐A), 40‐bp repeat in the 3′‐untranslated region of the dopamine transporter gene (DAT‐1), and 48‐bp repeat in the exon 3 of the dopamine receptor 4 gene (DRD4) were examined. Significant associations between cold pain tolerance and DAT‐1 (p = 0.008) and MAO‐A (p = 0.024) polymorphisms were found. Specifically, tolerance was shorter for carriers of allele 10 and the rarer allele 11, as compared to homozygous for allele 9, and for carriers of allele 4 as compared to homozygous for allele 3, respectively. These results, together with the known function of the investigated candidate gene polymorphisms, suggest that low dopaminergic activity can be associated with high pain sensitivity and vice versa.

Factors affecting – And relationships between – Different modes of endogenous pain modulation in healthy volunteers

Endogenous analgesia (EA) can be reflected by diffuse noxious inhibitory control (DNIC), non‐noxious inhibitory control (NNIC) and habituation to repeated painful stimuli. However, the coexistence of these phenomena in a given individual and the degree to which various factors predict their magnitudes have not been fully investigated. Using experimental paradigms of DNIC, NNIC and habituation, the present study explored the relationships between – and the contribution factors to – the magnitude of EA exhibited by healthy volunteers (n = 191; 104 F, 87 M) exposed to these three experimental paradigms. Each subject was assigned to all three paradigms (DNIC‐tested by co‐administering repeated short painful heat stimuli and a conditioning tonic cold pain stimulation; NNIC – tested similarly with the exception of using a painless conditioning stimulation; habituation – tested by applying repeated painful heat stimuli only) in a random order. Pain intensities decreased from baseline in all three paradigms. However, DNIC produced significantly more pain reduction than the other two modes (RM‐ANOVA). The magnitude of pain reduction of DNIC was found to be highly correlated with that of NNIC and habituation (r = 0.56, p < 0.001 for both correlations). A hierarchical regression analysis showed that baseline (p < 0.001) and conditioning pain scores (p = 0.043) predicted the magnitude of DNIC. A gender split analysis showed that conditioning pain scores served as a predictive factor for men only. Conclusions: Under these experimental conditions, different EA conditions seem to be related to each other. High initial pain intensities predict ‘effective’ DNIC and habituation, whereas intensity of the conditioning stimulus determines the magnitude of DNIC in men only.

Predicting the analgesic effect to oxycodone by 'static' and 'dynamic' quantitative sensory testing in healthy subjects.

&NA; The large inter‐individual variability in the magnitude of analgesia in response to opioids and the high prevalence of adverse events associated with their use underline the clinical importance of being able to predict who will or will not respond to opioid treatment. The present study used both static and dynamic quantitative sensory testing (QST) on 40 healthy volunteers in order to test whether this methodology can predict the analgesic effects of oral oxycodone, as compared to a placebo, on latency to onset, pain intensity, and tolerance to the cold pressor test (CPT). Static QST consisted of measuring heat and cold pain thresholds. Dynamic QST included measurements of the magnitude of the diffuse noxious inhibitory control (DNIC)‐like effect and of temporal summation (TS). Results showed that oxycodone, but not the placebo, significantly elevated the latency and tolerance to cold pain and significantly reduced pain intensity. The static QST results showed that heat pain thresholds predicted the magnitude of reduction in pain intensity in response to oxycodone treatment (F(1,22) = 5.63, p = 0.027, R2 = 0.17). The dynamic QST results showed that TS predicted the effect of oxycodone on the tolerance to CPT (F(1,38) = 9.11, p = 0.005, R2 = 0.17). These results suggest that both static and dynamic QST have the potential to be useful in the prediction of the response to opioid treatment.

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.

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.

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.

331 ASSOCIATION BETWEEN GENETIC POLYMORPHISMS IN DOPAMINE NEUROTRANSMITTER PATHWAY GENES AND PAIN RESPONSE IN HEALTHY HUMAN: A FAMILY‐BASED STUDY

Results: As expected, the effects of pain catastrophizing were mediated by the experienced threat of pain. Participants experiencing low threat reported less pain in the ‘observer’ and ‘observer/control’ conditions, but displayed equal amounts of facial pain expression. Participants experiencing high threat reported equal amounts of pain in all conditions, but displayed more facial pain expression in the ‘observer’ condition. Conclusions: Perceived control of another appears to reduce pain of low pain catastrophizers only, while high pain catastrophizers increase facial pain expression, perhaps attempting to solicit social support. These results may reconcile the assumed divergence between the cognitive appraisal and communal coping model of pain catastrophizing.