Thomas Graven-Nielsen

Sensitization in patients with painful knee osteoarthritis

&NA; Pain is the dominant symptom in osteoarthritis (OA) and sensitization may contribute to the pain severity. This study investigated the role of sensitization in patients with painful knee OA by measuring (1) pressure pain thresholds (PPTs); (2) spreading sensitization; (3) temporal summation to repeated pressure pain stimulation; (4) pain responses after intramuscular hypertonic saline; and (5) pressure pain modulation by heterotopic descending noxious inhibitory control (DNIC). Forty‐eight patients with different degrees of knee OA and twenty‐four age‐ and sex‐matched control subjects participated. The patients were separated into strong/severe (VAS ≥ 6) and mild/moderate pain (VAS < 6) groups. PPTs were measured from the peripatellar region, tibialis anterior (TA) and extensor carpi radialis longus muscles before, during and after DNIC. Temporal summation to pressure was measured at the most painful site in the peripatellar region and over TA. Patients with severely painful OA pain have significantly lower PPT than controls. For all locations (knee, leg, and arm) significantly negative correlations between VAS and PPT were found (more pain, more sensitization). OA patients showed a significant facilitation of temporal summation from both the knee and TA and had significantly less DNIC as compared with controls. No correlations were found between standard radiological findings and clinical/experimental pain parameters. However, patients with lesions in the lateral tibiofemoral knee compartment had higher pain ratings compared with those with intercondylar and medial lesions. This study highlights the importance of central sensitization as an important manifestation in knee OA.

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.

Inhibition of motor system excitability at cortical and spinal level by tonic muscle pain

OBJECTIVE To assess whether the motor system excitability can be modified by experimental tonic pain induced either in muscles or in subcutis. METHODS Transcranial magnetic stimulation of the left primary motor cortex was used to record motor evoked potentials (MEPs) from the right abductor digiti minimi (ADM) muscle. Recordings were made before, during and after experimental pain induced by (1) injection of hypertonic (5%) saline into the right ADM, the right first dorsal interosseum (FDI) and the left ADM muscles, and (2) injection of hypertonic saline in the subcutaneous region of the right ADM. Both MEPs and H-reflex were recorded also from the right flexor carpi radialis (FCR) before, during and after muscle pain. RESULTS MEPs recorded from the ADM muscle were significantly reduced in amplitude during pain induced in the right ADM and right FDI muscles, but not during pain in the left ADM muscle or during subcutaneous pain. This inhibitory effect was observed during the peak-pain and persisted also after the disappearance of the pain sensation. In the FCR muscle, the MEP inhibition was observed during the peak-pain, while a significant reduction of the H-reflexs amplitude was observed starting 1 min after the peak-pain. CONCLUSIONS Tonic muscle pain can inhibit the motor system. The motor cortex inhibition observed at an early phase is followed by a reduction of the excitability of both cortical and spinal motoneurones.

Generalised muscular hyperalgesia in chronic whiplash syndrome

The whiplash syndrome has immense socio-economic impact. Despite extensive studies over the past years, the mechanisms involved in maintaining the pain in chronic whiplash patients are poorly understood. The aim of the present experimental study was to examine the muscular sensibility in areas within and outside the region involved in the whiplash trauma. Eleven chronic whiplash patients and 11 sex and age matched control subjects were included in the study. Before the experiment, the whiplash patients had pain in the neck and shoulder region with radiating pain to the arm. Five patients reported pain that was more widespread. The somatosensory sensibility in the areas over the infraspinatus, brachioradial, and anterior tibial muscles was assessed by pressure stimulation, pin-prick stimulation, and cotton swap stimulation. Infusion of hypertonic saline (5.85%, 0.5 ml) into the infraspinatus and anterior tibial muscles was performed to assess the muscular sensibility and referred pain pattern. The saline-induced muscle pain intensity was assessed on a continuous visual analogue scale (VAS). The distribution of pain was drawn on an anatomical map. The pressure pain thresholds were significantly lower in patients (P<0. 01) compared with controls: infraspinatus (mean 152.2 vs. 172.7 kPa), brachioradial (mean 70.0 vs. 363.8 kPa), and anterior tibial muscle (mean 172.7 vs. 497.8 kPa). The skin sensibility to pin-prick stimulation and cotton swap stimulation was not different between patients and controls. Infusion of hypertonic saline caused significantly higher VAS scores with longer duration in patients compared to control subjects (P<0.01). The area under the VAS-time curve was significantly (P<0.01) increased in patients compared to control subjects after injection into the infraspinatus muscle (mean 4138.1 vs. 780.0 cm s) and anterior tibial muscle (mean 4370.8 vs. 978.7 cm s). The saline infusion caused local pain defined as pain located around the injection site and referred pain areas not included in the local pain area. The area of local and referred pain were significantly larger in patients compared to control subjects (P<0.01). In the control group, the referred pain areas to infusion of hypertonic saline into the anterior tibial muscle were found at the dorsal aspect of the ankle. In contrast, the areas of referred pain were quite widespread in the patient group with both distal and proximal referred pain areas. In the present study, muscular hyperalgesia and large referred pain areas were found in patients with chronic whiplash syndrome compared to control subjects both within and outside the traumatised area. The findings suggest a generalised central hyperexcitability in patients suffering from chronic whiplash syndrome. This indicates that the pain might be considered as a neurogenic type of pain, and new pharmacological treatments should be investigated accordingly.

Osteoarthritis and its association with muscle hyperalgesia: an experimental controlled study.

&NA; Hypertonic saline effectively excites muscle nociceptors. Muscle hyperalgesia was assessed in osteoarthritis (OA) by intramuscular infusion of 0.5 ml hypertonic saline (6%) into the tibialis anterior muscle in humans. Patients (n=14) with OA in the lower extremities were compared with an equal number of age‐ and sex‐matched healthy controls. Ten of the 14 OA patients had pain in the knee joint as the most common presenting complaint. Visual analogue scale (VAS) pain intensity and assessment of pain areas were recorded before infusion and immediately, 2, 5, 10 and 20 min after infusion, and then every 10 min, until the pain vanished. The mean pain offset time in OA patients (11.3±7.9 min) was larger as compared with the control subjects (6.04±2.1 min) (P=0.025). OA patients had increased pain intensity VAS after the infusion in the right leg compared with controls (P<0.05). Referred and radiating pain areas at 2 min post‐infusion increased in OA patients and not in controls as compared with the local pain areas (P<0.05). It is concluded that muscle hyperalgesia and extended pain areas might be due to central sensitization caused by painful osteoarthritis.

Effects of experimental muscle pain on muscle activity and co-ordination during static and dynamic motor function

The relation between muscle pain, muscle activity, and muscle co-ordination is still controversial. The present human study investigates the influence of experimental muscle pain on resting, static, and dynamic muscle activity. In the resting and static experiments, the electromyography (EMG) activity and the contraction force of m. tibialis anterior were assessed before and after injection of 0.5 ml hypertonic saline (5%) into the same muscle. In the dynamic experiment, injections of 0.5 ml hypertonic saline (5%) were performed into either m. tibialis anterior (TA) or m. gastrocnemius (GA) and the muscle activity and co-ordination were investigated during gait on a treadmill by EMG recordings from m. TA and m. GA. At rest no evidence of EMG hyperactivity was found during muscle pain. The maximal voluntary contraction (MVC) during muscle pain was significantly lower than the control condition (P < 0.05). During a static contraction at 80% of the pre-pain MVC muscle pain caused a significant reduction in endurance time (P < 0.043). During dynamic contractions, muscle pain resulted in a significant decrease of the EMG activity in the muscle, agonistic to the painful muscle (P < 0.05), and a significant increase of the EMG activity of the muscle, antagonistic to the painful muscle (P < 0.05). Muscle pain seems to cause a general protection of painful muscles during both static and dynamic contractions. The increased EMG activity of the muscle antagonistic to the painful muscle is probably a functional adaptation of muscle co-ordination in order to limit movements. Modulation of muscle activity by muscle pain could be controlled via inhibition of muscles agonistic to the movement and/or excitation of muscles antagonistic to the movement. The present results are in accordance with the pain-adaptation model (Lund, J.P., Stohler, C.S. and Widmer, C.G. In: H. Vaerøy and H. Merskey (Eds.), Progress in Fibromyalgia and Myofascial Pain. Elsevier, Amsterdam, 1993, pp. 311-327.) which predicts increased activity of antagonistic muscle and decreased activity of agonistic muscle during experimental and clinical muscle pain.

Assessment of mechanisms in localized and widespread musculoskeletal pain

The aim of this Review is to give a short presentation of the manifestations, assessment methods, and mechanisms underlying localized and widespread musculoskeletal pain, deep somatic tissue hyperalgesia and chronification. Hyperalgesia can be explained by increased pain sensitivity of nociceptors located in deep tissue (peripheral sensitization) or by increased responses from dorsal horn neurons (central sensitization). The spreading of pain and sensitization is related to increased synaptic activity in central neurons and to changes in descending control from supraspinal centers. Manifestations related to the different aspects of sensitization can be assessed quantitatively using sensory tests, such as pressure algometry (quantitative palpation) and cuff-algometry. Repeated pressure stimulation can evaluate the degree of temporal summation, which is a proxy for the level of central sensitization, as is expanded referred muscle pain area. The transition of acute localized musculoskeletal pain into chronic widespread pain is related to the progression of peripheral and central sensitization. This sensitization for the chronification of pain should be assessed by adequate pain biomarkers. Furthermore, pain prevention should target early intervention strategies and new anti-hyperalgesic compounds should be developed.

The peripheral apparatus of muscle pain: evidence from animal and human studies.

The peripheral apparatus of muscle pain consists of nociceptors that can be excited by endogenous substances and mechanical stimuli. Histologically, the nociceptors are free nerve endings supplied by group III (thin myelinated) and group IV (nonmyelinated) afferents with conduction velocities less than 30 m/s. At the molecular level, nociceptors have receptors for algesic substances, such as bradykinin, serotonin, and prostagladin E2. The purinergic receptors and tetrodotoxin-resistant sodium channels might be new important targets for the treatment of muscle pain. Algesic substances (capsaicin, bradykinin, serotonin, potassium chloride, and hypertonic saline) and other stimuli (ischemia, strong mechanical stimuli, and electrical stimuli) have been shown to induce nociception from muscle in animals and muscle pain in humans. Muscle nociceptors can be sensitized to chemical and mechanical stimuli. Contrary to a former belief, the sensitization is not an unspecific process; rather, it is caused by endogenous algesic substances binding to highly specific receptor molecules in the membrane of the nociceptive ending. For example, animal studies showed that serotonin sensitizes muscle nociceptors to chemical and mechanical stimuli. Later, human studies showed that serotonin combined with bradykinin induces muscle hyperalgesia to pressure. The sensitization process by endogenous substances that are likely to be released during trauma or inflammatory injury is probably the best established peripheral mechanism for muscle tenderness and hyperalgesia.

Generalized deep-tissue hyperalgesia in patients with chronic low-back pain

Some chronic painful conditions including e.g. fibromyalgia, whiplash associated disorders, endometriosis, and irritable bowel syndrome are associated with generalized musculoskeletal hyperalgesia. The aim of the present study was to determine whether generalized deep‐tissue hyperalgesia could be demonstrated in a group of patients with chronic low‐back pain with intervertebral disc herniation. Twelve patients with MRI confirmed lumbar intervertebral disc herniation and 12 age and sex matched controls were included. Subjects were exposed to quantitative nociceptive stimuli to the infraspinatus and anterior tibialis muscles. Mechanical pressure (thresholds and supra‐threshold) and injection of hypertonic saline (pain intensity, duration, distribution) were used. Pain intensity to experimental stimuli was assessed on a visual analogue scale (VAS). Patients demonstrated significantly higher pain intensity (VAS), duration, and larger areas of pain referral following saline injection in both infraspinatus and tibialis anterior. The patients rated significantly higher pain intensity to supra‐threshold mechanical pressure stimulation in both muscles. In patients, the pressure pain‐threshold was lower in the anterior tibialis muscle compared to controls. In conclusion, generalized deep‐tissue hyperalgesia was demonstrated in chronic low‐back pain patients with radiating pain and MRI confirmed intervertebral disc herniation, suggesting that this central sensitization should also be addressed in the pain management regimes.

Quantification of local and referred muscle pain in humans after sequential i.m. injections of hypertonic saline

Abstract The aim of the present study was to test (1) whether muscle pain is influenced by temporal and spatial summation, and (2) whether sequential noxious muscle stimuli applied at hourly interstimulus‐intervals could produce an increased sensation of pain due to central hyperexcitability. In the study eleven healthy men were exposed to computer‐controlled intramuscular infusion of saline (5%) given over 20 s in m. tibialis anterior (m. TA). The intensities of local and referred pain were assessed by recordings on visual analogue scales (VAS), and the areas of local pain (around the injection site) and referred pain (outside the local pain area) were localised by the subject. Three experiments were performed. Experiment 1: Each subject participated in three tests separated by one week: (a) bolus (0.4 ml saline) infusion at one site; (b) four sequential infusions (0.1 ml saline) given at 90‐s interstimulus‐intervals at one site; and (c) four sequential infusions (0.1 ml saline) given at 360‐s interstimulus‐intervals at one site. Experiment 2: This was performed as experiment 1, but the infusions were given at spatially separated sites. Experiment 3: Hypertonic saline (0.1 ml) was injected one, four and 24 h after the sequential infusions (90‐s interstimulus‐intervals) given at spatially separated sites. The highest VAS peak and the largest local and referred pain areas were found after the bolus infusions. Compared to the first infusion, significant increases were found in the VAS peak, the size of the local pain area, and the size of the referred pain area (non‐significant) after the four sequential infusions given at 90‐s interstimulus‐intervals (temporal summation). Four spatially separated infusions given simultaneously produced a higher VAS peak, a larger local pain area, and a larger referred pain area (non‐significant) compared to one infusion (spatial summation). The infusion given 4 h after the sequential infusions tended to produce an increase in the referred pain area and in the pain intensity. In all three experiments significant correlations were found between the VAS peak and the size of the local (R=0.64, P<0.0001, n=231) and referred (R=0.47, P<0.0001, n=231) pain areas. Based on the above results it can be concluded that experimental muscle pain is influenced by temporal and spatial summation.