Jan Sörensen

Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients

&NA; Central mechanisms related to referred muscle pain and temporal summation of muscular nociceptive activity are facilitated in fibromyalgia syndrome (FMS) patients. The present study assessed the effects of an NMDA‐antagonist (ketamine) on these central mechanisms. FMS patients received either i.v. placebo or ketamine (0.3 mg/kg, Ketalar®) given over 30 min on two separate occasions. Habitual pain intensity was assessed on a visual analogue scale (VAS). Initially, 29 FMS patients received ketamine or isotonic saline to determine which patients were ketamine responders (>50% decrease in pain intensity at rest by active drug on two consecutive VAS assessments). Fifteen out of 17 ketamine‐responders were included in the second part of the study. Before and after ketamine or placebo, experimental local and referred pain was induced by intramuscular (i.m.) infusion of hypertonic saline (0.7 ml, 5%) into the tibialis anterior (TA) muscle. The saline‐induced pain intensity was assessed on an electronic VAS, and the distribution of pain drawn by the subject. In addition, the pain threshold (PT) to i.m. electrical stimulation was determined for single stimulus and five repeated (2 Hz, temporal summation) stimuli. The pressure PT of the TA muscle was determined, and the pressure PT and pressure pain tolerance threshold were determined at three bilaterally located tenderpoints (knee, epicondyle, and mid upper trapezius). VAS scores of pain at rest were progressively reduced during ketamine infusion compared with placebo infusion. Pain intensity (area under the VAS curve) to the post‐drug infusion of hypertonic saline was reduced by ketamine (−18.4±0.3% of pre‐drug VAS area) compared with placebo (29.9±18.8%, P<0.02). Local and referred pain areas were reduced by ketamine (−12.0±14.6% of pre‐drug pain areas) compared with placebo (126.3±83.2%, P<0.03). Ketamine had no significant effect on the PT to single i.m. electrical stimulation. However, the span between the PT to single and repeated i.m. stimuli was significantly decreased by the ketamine (−42.3±15.0% of pre‐drug PT) compared with placebo (50.5±49.2%, P<0.03) indicating a predominant effect on temporal summation. Mean pressure pain tolerance from the three paired tenderpoints was increased by ketamine (16.6±6.2% of pre‐drug thresholds) compared with placebo (−2.3±4.9%, P<0.009). The pressure PT at the TA muscle was increased after ketamine (42.4±9.2% of pre‐drug PT) compared with placebo (7.0±6.6%, P<0.011). The present study showed that mechanisms involved in referred pain, temporal summation, muscular hyperalgesia, and muscle pain at rest were attenuated by the NMDA‐antagonist in FMS patients. It suggested a link between central hyperexcitability and the mechanisms for facilitated referred pain and temporal summation in a sub‐group of the fibromyalgia syndrome patients. Whether this is specific for FMS patients or a general phenomena in painful musculoskeletal disorders is not known.

Pain Analysis in Patients with Fibromyalgia: Effects of intravenous morphine, lidocaine, and ketamine

Pain intensity, muscle strength, static muscle endurance, pressure pain threshold, and pain tolerance at tender points and control points were assessed in 31 patients with fibromyalgia (FM), before and after intravenous administration of morphine (9 patients), lidocaine (11 patients), and ketamine (11 patients). The three different studies were double-blind and placebo-controlled. The patients were classified as placebo-responders, responders (decrease in pain intensity by > 50%) and non-responders. The morphine test did not show any significant changes. The lidocaine test showed a pain decrease during and after the infusion. The ketamine test showed a significant reduction in pain intensity during and after the test period. Tenderness at tender points decreased and endurance increased significantly, while muscle strength remained unchanged. The present results support the hypothesis that the NMDA receptors are involved in pain mechanisms in fibromyalgia. These findings also suggest that central sensitization is present in FM and that tender points represent secondary hyperalgesia.

Increase in muscle nociceptive substances and anaerobic metabolism in patients with trapezius myalgia: microdialysis in rest and during exercise.

&NA; Local metabolic changes are suggested to be involved in muscle pain development in humans. Nineteen women with chronic work‐related trapezius myalgia (TM) and 20 healthy female controls (CON) were studied during baseline rest, 20 min repetitive low‐force exercise, and 120 min recovery. Interstitial serotonin (5‐HT), glutamate, lactate, pyruvate, and blood flow were determined by microdialysis in the trapezius muscle. Baseline pressure pain threshold (PPT) was lower (143±18 (TM) vs. 269±17 (CON) kPa) (mean±SEM), pain intensity (visual analogue scale, VAS) higher (33±5 vs. 2±1 mm), muscle 5‐HT higher (22.9±6.7 vs. 3.8±1.3 nmol/l), and glutamate higher (47±3 vs. 36±4 μmol/l) in TM than in CON (all P<0.05), whereas muscle blood flow was similar in groups. Furthermore, muscle pyruvate was higher (180±15 vs. 135±12 μmol/l) and lactate higher (4.4±0.3 vs. 3.1±0.3 mmol/l) in TM than in CON (P<0.001). In response to exercise, VAS and glutamate increased in both TM and CON (all P<0.05). In TM only, lactate and pyruvate increased significantly (P<0.02), whereas blood flow increased to similar levels in both groups. During the initial 20 min recovery period, blood flow remained increased in TM (P<0.005) whereas it decreased to baseline levels in CON. In conclusion, patients with chronic work‐related TM have increased levels of muscle 5‐HT and glutamate that were correlated to pain intensity (r=0.55, P<0.001) and PPT (r=−0.47, P<0.001), respectively. In addition, TM was associated with increased anaerobic metabolism, whereas a normal rise in blood flow was seen with exercise. These findings indicate that peripheral nociceptive processes are active in work‐related TM.

Morphine responsiveness in a group of well-defined multiple sclerosis patients: a study with i.v. morphine.

Pain in multiple sclerosis (MS) is more common than has previously been believed. About 28% of all MS patients suffer from central pain (CP), a pain that is difficult to treat. In the present study we have investigated the responsiveness of this pain to morphine. Fourteen opioid‐free patients (eight woman and six men) with constant, non‐fluctuating, long‐lasting CP caused by MS were investigated. Placebo (normal saline), morphine and naloxone were given intravenously in a standardized manner. The study design was non‐randomized, single blind and placebo controlled. Ten patients experienced less than 50% pain reduction by placebo and less than 50% pain reduction by morphine. Four patients were opioid responders, i.e. had minimal or no effect on pain by placebo, >50% pain reduction after morphine and >25% pain increase after naloxone, given intravenously following morphine. However, this response was obtained after high doses of morphine (43 mg, 47 mg, 50 mg and 25 mg; mean 41 mg). Thus, compared with nociceptive pain, only a minority of the patients with CP due to MS responded to morphine and only at high doses. The present results are in accord with experimental studies indicating that neuropathic pain is poorly responsive but not totally unresponsive to opioids. The results do not support the routine use of strong opioids in MS patients with CP.

Increased levels of interstitial potassium but normal levels of muscle IL-6 and LDH in patients with trapezius myalgia

Abstract The mechanisms behind the development of work‐related trapezius pain are suggested to involve both peripheral and central components, but the specific contribution of alterations in muscle nociceptive and other substances is not clear. Female patients with chronic trapezius myalgia (N=19; TM) and female controls (N=20; CON) were studied at rest, during 20 min repetitive low‐force exercise and recovery, and had their interstitial concentrations of potassium (K+), lactate dehydrogenase (LDH), interleukin‐6 (IL‐6) and collagen turnover determined in the trapezius muscle by the microdialysis technique. K+ levels were at all time points higher in TM than in CON (P<0.0001). Baseline levels of LDH and IL‐6 were similar in both groups. In response to exercise pain intensity, rated perceived exertion, and the concentrations of K+, LDH and IL‐6 increased significantly in both groups. [K+] immediately decreased to baseline levels in CON but remained elevated during the first 20 min of recovery in TM (P<0.01) whereafter it returned to baseline level. In all subjects taken together mean [K+] correlated negatively with pressure pain threshold of trapezius (P<0.001), positively with mean pain intensity VAS (P<0.001) and mean perceived exertion (P<0.001). Rises in muscle LDH and IL‐6 as well as the anabolic ratio for collagen type I was not significantly different between groups. In conclusion, patients with chronic pain in the trapezius muscle had increased levels of interstitial potassium. This finding could be causally related to myalgia or secondary to pain due to deconditioned muscle or altered muscle activity pattern.

The promise of N-methyl-D-aspartate receptor antagonists in fibromyalgia.

There is strong evidence that intravenous administration of ketamine following a standardized protocol could be used as a diagnostic test for a central sensitization in the central nervous system in patients with FM. The combination of a weak opioid and an NMDA-receptor antagonist with few side effects is presently a promise for treatment of pain in a subgroup of patients with FM. The response to intravenously administered ketamine may help select patients for this treatment modality.

Widespread pain hypersensitivity and facilitated temporal summation of deep tissue pain in whiplash associated disorder: an explorative study of women.

OBJECTIVE Widespread deep tissue pain hyperalgesia was evaluated in women with chronic whiplash associated disorder (n = 25) and controls (n = 10) using computerized cuff pressure algometry and hypertonic saline infusion. METHODS A pneumatic double-chamber cuff was placed around: (i) the arm and (ii) the leg. Cuff inflation rate was constant and the pain intensity was registered continuously on a visual analogue scale (VAS); thresholds of detection and tolerance were extracted. For assessment of spatial summation the protocol was repeated with a single-chamber cuff inflated around the leg. Temporal summation of pain was assessed from the leg with constant cuff pressure stimulation at 2 different pressure intensities for 10 min. Hypertonic saline was infused in the tibialis anterior muscle. RESULTS Cuff pressure pain thresholds were lower in subjects with whiplash associated disorder compared with controls (p < 0.05). Tonic pressure stimulation evoked higher maximal VAS and larger areas under the VAS curve in subjects with whiplash associated disorder compared with controls (p < 0.05). The pain threshold and tolerance were higher during single cuff than double cuff stimulation. The area under the VAS curve after intramuscular saline infusion was larger in whiplash associated disorder (p < 0.05). CONCLUSION The results indicated widespread hyperalgesia in chronic whiplash associated disorder and facilitated temporal summation outside the primary pain area, suggesting involvement of central sensitization.

The Responses to Pharmacological Challenges and Experimental Pain in Patients With Chronic Whiplash-associated Pain

Objectives:This study evaluates the analgesic responses to intravenous administration of morphine, lidocaine, and ketamine and their relations to duration of chronic pain after whiplash trauma. In addition, experimental muscle pain sensitivity and its correlation to pain duration and pharmacological responses were assessed. Methods:Thirty-three patients with diagnosed whiplash-associated disorder grade II in the chronic stage, according to the Quebec classification, were included. The pharmacological evaluation was performed in a randomized, double-blind, cross-over design and consisted of a 30-minute period of intravenous administration of morphine (0.3 mg/kg), lidocaine (5 mg/kg), ketamine (0.3 mg/kg), or placebo (isotonic saline). Intensity ratings of habitual pain on a visual analogue scale were taken before, during, and after the infusion. The patients were classified as nonresponders, placebo-responders, or responders (minimum 50% decrease of pain intensity) of the drugs. Pressure pain thresholds and intramuscular and cutaneous electrical stimulation pain thresholds were measured. The pain intensity during experimental muscle pain by intramuscular hypertonic saline was also recorded. Experimental pain assessments were performed on the lower legs outside the habitual painful area. Results:Thirty patients completed the study; 2 were placebo responders and 10 were nonresponders. Of 18 responders, there were 15 morphine responders, 11 lidocaine responders, and 14 ketamine responders. In the patients with whiplash-associated disorder duration less than 2 years, 7 responded to morphine, 5 to lidocaine, and 8 to ketamine. In the patients with pain duration longer than 2 years, 8 responded to morphine, 6 to lidocaine, and 6 to ketamine. Thus, no pattern with respect to pain duration was found. Seventeen patients participated in the experimental pain assessment, and no significant differences in the variables of the intramuscular and cutaneous stimulation and intramuscular-induced pain with respect to response to the pharmacological challenges or whiplash-associated disorder duration existed. Discussion:The pharmacological challenges identified subgroups of patients with chronic whiplash-associated disorder that might be considered before instituting therapeutic interventions or research. However, the pattern of responses to the pharmacological challenges did not show any clear relationships with pain duration or the experimental pain tests.

What Factors Influence the Health Status of Patients with Rheumatoid Arthritis Measured by the SF-12v2 Health Survey and the Health Assessment Questionnaire?

Objective. The Health Assessment Questionnaire Disability Index (HAQ) is a widely used outcome measure in rheumatoid arthritis (RA), whereas the SF-12v2 Health Survey (SF-12) was introduced recently. We investigated how the HAQ and SF-12 were associated with socio-demographic, lifestyle, and disease- and treatment-related factors in patients with RA. Methods. In RA patients from 11 Danish centers, clinical and patient-reported data, including the HAQ and SF-12, were collected. Three multiple linear regression models were estimated, with the HAQ, SF-12 physical component score (PCS), and SF-12 mental component score (MCS) as outcome and sociodemographic, lifestyle, and RA-related treatment and comorbidity characteristics as explanatory variables. Results. In total, 3156 (85%) of 3704 invited patients participated — 75% women, 76% rheumatoid factor-positive, median age 61 years (range 15–93 yrs), disease duration 7 years (range 0–68 yrs), Disease Activity Score on 28 joints (DAS28) 2.97 (range 0.96–8.61), HAQ score 0.63 (range 0–3), SF-12 PCS 56 (range 6–99), and SF-12 MCS 57 (range 16–99). Variation in HAQ was associated with 12 of 15 possible variables (R2 0.41), in PCS and MCS with 6 of 15 variables (R2 0.02 and 0.05). Patients with moderate to high DAS28 and ≥ 3 comorbid conditions had consistently worse HAQ and SF-12 scores compared to the reference groups, while weekly exercise was associated with better scores compared to no exercise. Conclusion. The HAQ was more sensitive to differences in demographic, lifestyle, and disease- and treatment-related factors than the SF-12. The established clinical value and feasibility of the HAQ highlights its advantages over the SF-12 in describing health status in RA.

Does Clinical Remission Lead to Normalization of EQ-5D in Patients with Rheumatoid Arthritis and Is Selection of Remission Criteria Important?

Objective. To compare health-related quality of life (HRQOL) of patients with rheumatoid arthritis (RA) to that of the general population and to investigate the association with disease activity, focusing on different clinical remission criteria. Methods. EQ-5D data from 3156 patients with RA from 11 Danish centers were compared with Danish EQ-5D population norms (n = 16,136). The Disease Activity Score (DAS28) and the Clinical Disease Activity Index score (CDAI) were used as definitions of disease activity and clinical remission. The score difference (ΔEQ-5D) was calculated in each patient as the difference from the age and sex-matched general population and adjusted for age, marital status, education, body mass index, smoking, exercise habits, disease duration, IgM-rheumatoid factor status, joint surgery, extraarticular features, treatment, and comorbidity in multiple linear regression models. Results. 37% vs 22% fulfilled the DAS28 and CDAI remission criteria, respectively. The ΔEQ-5D values for women/men in clinical remission were DAS28 0.05/0.06 vs CDAI 0.01/0.02; low disease activity: DAS28 0.12/0.13 vs CDAI 0.11/0.14; moderate disease activity: DAS28 0.18/0.20 vs CDAI 0.20/0.23; and high disease activity: DAS28 0.38/0.28 vs CDAI 0.33/0.26. Adjusting for confounders reduced the ΔEQ-5D values between 0 and 0.04 units. Conclusion. Patients with RA had worse EQ-5D scores than the general population, and the difference was strongly associated with disease activity. The EQ-5D score for patients in clinical remission approached that of the general population, suggesting that strict treatment goals are critical in order to achieve near-normal HRQOL in patients with RA.