[Pain and bone metastases]. / Douleur et métastases osseuses.

Average 20% of the cancer patients will have bone metastasis most of time painful and with variable clinical expressions. Due to animal models, the bone metastasis pain is better known and it explains the different treatments mechanisms. After a suitable evaluation of the pain, several therapeutic approaches can be suggested. In addition to the classical analgesics, several medications are known to be efficient in few indications like neuropathic pain. Besides a local surgery, an external radiotherapy or an interventional radiology treatment can often be useful along with a medical treatment. When there is a bone progression, the anti-cancer treatment by chemotherapy, hormonotherapy or targeted therapies must always be reviewed, because if efficient it could have an analgesic action.

Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia.

Non-invasive unilateral repetitive transcranial magnetic stimulation (rTMS) of the motor cortex induces analgesic effects in focal chronic pain syndromes, probably by modifying central pain modulatory systems. Neuroimaging studies have shown bilateral activation of a large number of structures, including some of those involved in pain processing, suggesting that such stimulation may induce generalized analgesic effects. The goal of this study was to assess the effects of unilateral rTMS of the motor cortex on chronic widespread pain in patients with fibromyalgia. Thirty patients with fibromyalgia syndrome (age: 52.6 +/- 7.9) were randomly assigned, in a double-blind fashion, to two groups, one receiving active rTMS (n = 15) and the other sham stimulation (n = 15), applied to the left primary motor cortex in 10 daily sessions. The primary outcome measure was self-reported average pain intensity over the last 24 h, measured at baseline, daily during the stimulation period and then 15, 30 and 60 days after the first stimulation. Other outcome measures included: sensory and affective pain scores for the McGill pain Questionnaire, quality of life (assessed with the pain interference items of the Brief Pain Inventory and the Fibromyalgia Impact Questionnaire), mood and anxiety (assessed with the Hamilton Depression Rating Scale, the Beck Depression Inventory and the Hospital Anxiety and Depression Scale). We also assessed the effects of rTMS on the pressure pain threshold at tender points ipsi- and contralateral to stimulation. Follow-up data were obtained for all the patients on days 15 and 30 and for 26 patients (13 in each treatment group) on day 60. Active rTMS significantly reduced pain and improved several aspects of quality of life (including fatigue, morning tiredness, general activity, walking and sleep) for up to 2 weeks after treatment had ended. The analgesic effects were observed from the fifth stimulation onwards and were not related to changes in mood or anxiety. The effects of rTMS were more long-lasting for affective than for sensory pain, suggesting differential effects on brain structures involved in pain perception. Only few minor and transient side effects were reported during the stimulation period. Our data indicate that unilateral rTMS of the motor cortex induces a long-lasting decrease in chronic widespread pain and may therefore constitute an effective alternative analgesic treatment for fibromyalgia.

Are oral cannabinoids safe and effective in refractory neuropathic pain?

Although cannabinoids have anti-hyperalgesic effects in animal models of nerve injury, there are currently very few prospective trials of the efficacy of cannabinoids in neuropathic pain in humans. This open label prospective study investigated the safety, tolerability and analgesic benefit of oral Delta-9-tetrahydrocannabinol (THC) titrated to a maximal dosage of 25 mg/day in 8 consecutive patients with chronic refractory neuropathic pain. Spontaneous ongoing and paroxysmal pain, allodynia and paresthesias were assessed. The sensory and affective components of pain using the McGill pain questionnaire, quality of life, mood, anxiety and functionality were also evaluated. Seven patients suffered from side effects necessitating premature arrest of the drug in 5 of them. THC (mean dosage: 16.6+/-6.5 mg/day) did not induce any significant effects on ongoing and paroxysmal pain, allodynia, quality of life, anxiety/depression scores and functional impact of pain. These results do not support an overall benefit of THC in pain and quality of life in patients with refractory neuropathic pain.

Systemic lidocaine in pain due to peripheral nerve injury and predictors of response.

OBJECTIVE: To investigate the effects of IV lidocaine on spontaneous and evoked pain (allodynia and hyperalgesia) due to peripheral nerve injury (postherpetic neuralgia or nerve trauma) using quantitative sensory testing. METHOD: The authors randomized 22 patients to receive lidocaine 5 mg/kg IV during 30 minutes or placebo in a double-blind crossover design and 16 patients subsequently received mexiletine on an open basis titrated from 400 to 1,000 mg per day (mean 737 mg/day). RESULTS: Lidocaine induced a significant decrease in ongoing pain for up to 6 hours with a peak effect 60 to 120 minutes postinjection. The drug also decreased mechanical dynamic allodynia and static (punctate) mechanical allodynia/hyperalgesia, but not thermal allodynia and hyperalgesia. The effects of lidocaine and mexiletine on spontaneous pain intensity were significantly higher in patients with concomitant mechanical allodynia in comparison with those without allodynia. CONCLUSIONS: These data indicate modality-specific antihyperalgesic effects of IV lidocaine in patients with peripheral nerve injury. Patients with mechanical allodynia may be good candidates for treatment with local anesthetic-like drugs and possibly with other sodium-channel blockers.

[Pain in kidney disease]. / Douleur en néphrologie.

There are little data concerning the prevalence of pain and its intensity in the population suffering from kidney diseases. However, according to number of pathologies with a kidney impact, the sequellae of the kidney disease itself and the technology in this area, there is a risk for a high prevalence rate of either acute and/or chronic pain. This can be responsible for some degree of psychologic disturbances as a major impact on the quality of life. Pain management must be a challenge in this field as it may interfere with the kidney disease.

Long term effects of oral sustained release morphine on neuropsychological performance in patients with chronic non-cancer pain.

Morphine is increasingly used in patients with chronic non-cancer pain, but a major concern associated with chronic use relates to possible cognitive side-effects. The aim of this long-term prospective study was to evaluate the cognitive impact of oral sustained release morphine in patients with non-cancer pain. A battery of neuropsychological tests to explore attention, psychomotor speed and memory was administered. The effects of morphine on pain, quality of life, mood, subjective memory impairment and side-effects were also investigated. Evaluations were performed at baseline in patients free from opioids and then after 3, 6 and 12 months. Twenty-eight patients were included: 18 received oral sustained morphine (range 40-140 mg/day), ten patients stopped morphine prematurely because of side-effects or insufficient pain relief and were followed as a control group. There was no impairment of any neuropsychological variable over time in the morphine treated patients in comparison with the control group. Two measures of information processing speed - the Stroop interference score and the digit symbol test were improved at 6 and 12 months and there were significant correlations with the pain relief and improvement of mood. Self-reported memory impairment improved notably in responders to morphine. Morphine induced persisting effects on pain, and to a lesser extent on quality of life and mood. The visual analog scale score for side-effects increased at 12 months and essentially consisted of gastrointestinal disorders. This study demonstrates that 12 months treatment with oral morphine does not disrupt cognitive functioning in patients with chronic non-cancer pain and instead results in moderate improvement of some aspects of cognitive functioning, as a consequence of the pain relief and concomitant improvement of well-being and mood.

Effects of IV morphine in central pain: a randomized placebo-controlled study.

OBJECTIVE: To investigate the effects of IV morphine on central pain syndromes through quantitative sensory testing and to assess the long-term benefit of oral morphine. METHODS: After an initial open titration phase aiming to determine the maximal tolerated dosage of IV morphine, the efficacy of morphine infusion (9-30 mg; mean dosage, 16 mg) was assessed in a double-blind, placebo-controlled and crossover fashion in 15 patients with poststroke- (6 patients) or spinal cord injury- (9 patients) related pain. All of the patients subsequently received sustained oral morphine. RESULTS: Morphine significantly reduced the intensity of brush-induced allodynia but had no effect on other evoked pains (i.e., static mechanical and thermal allodynia/hyperalgesia). The effects of morphine on ongoing pain were not significantly different from those of the placebo, but 7 patients (46%) responded to morphine. There was a correlation between the effects of morphine on spontaneous pain and the decrease of the responses to suprathreshold thermal stimuli on the nonpainful contralateral side, suggesting that these effects were related to the general antinociceptive activity of the drug. The effects of IV morphine were correlated with those of oral morphine at 1 month, but only 3 patients (20%) were still taking morphine after 1 year. CONCLUSIONS: IV morphine induces analgesic effects on some components of central neuropathic pain syndromes, but only a minority of patients may benefit from long-term opioid treatment.

Local and remote effects of hypnotic suggestions of analgesia.

The present study was designed to further characterize hypnotic analgesia and particularly to examine whether the effects are due to a selective alteration of pain perception and are organized somatotopically. Thirty-two healthy volunteers participated in this study. Thermal detection thresholds for warmth and cool stimuli and heat pain thresholds were measured at both the upper and lower left limbs by means of a thermotest. Measurements were performed before, during and after a hypnotic session during which the subjects were administered a French adaptation of the Stanford Hypnotic Susceptibility Scale and then standardized suggestions of analgesia limited to the left foot. Heat pain thresholds were significantly increased at both the lower and upper limbs. Changes at the foot were positively correlated with the hypnotic susceptibility score, while, unexpectedly, changes at the hand were negatively correlated with the susceptibility score. Mean detection thresholds for warmth and cool stimuli were also altered at both the lower and upper limbs during hypnosis, but these modifications were correlated neither with susceptibility nor with the changes in heat pain threshold. These results indicate that hypnotic suggestions can selectively and somatotopically alter pain sensation in highly susceptible subjects. It is also suggested, however, that suggestions of analgesia can induce selective alterations of pain perception in poorly susceptible subjects, although these effects did not appear to be localized 'appropriately'.

Intravenous lidocaine in central pain: a double-blind, placebo-controlled, psychophysical study.

OBJECTIVE: To investigate the effects of systemic administration of lidocaine on different components of neuropathic central pains by quantitative sensory testing. METHODS: The efficacy of systemic lidocaine (5 mg/kg IV over 30 minutes) was evaluated in a double-blind, placebo-controlled, and cross-over fashion, on both spontaneous ongoing pain and evoked pains (allodynia and hyperalgesia) in 16 patients with chronic poststroke (n = 6) or spinal cord injury (n = 10) related pain. RESULTS: Lidocaine was significantly superior to the placebo (saline) in reducing the intensity of spontaneous ongoing pain for up to 45 minutes after the injection: 10 of 16 patients (62.5%) receiving lidocaine showed a significant reduction in spontaneous pain, whereas only six patients showed this after the placebo. Lidocaine also significantly reduced the intensity of brush-induced allodynia and mechanical hyperalgesia, but was no better than the placebo against thermal allodynia and hyperalgesia. In general, the side effects were moderate and consisted mainly of lightheadedness (44%). CONCLUSIONS: Systemic lidocaine can induce a significant and selective reduction of several components of pain caused by CNS injuries. The observed preferential antihyperalgesic and antiallodynic effects of this drug suggest a selective central action on the mechanisms underlying these evoked pains.

The effects of ketamine on the temporal summation (wind-up) of the R(III) nociceptive flexion reflex and pain in humans.

UNLABELLED: Animal studies have suggested that the temporal summation of nociceptive inputs might play a significant role in the development of central sensitization (i.e., hyperexcitability of central nociceptive neurons) and hyperalgesia via the activation of N-methyl-D-aspartate receptors. To further analyze these processes in humans, we evaluated the effects of small systemic doses of ketamine on the temporal summation (i.e., wind-up) of both the nociceptive flexion (R(III)) reflex and sensations of pain in six healthy volunteers. The R(III) reflex was recorded from the biceps femoris and was elicited by electrical stimulation of the sural nerve. First, the recruitment (stimulus/response) curve for the reflex was built using stimuli up to the pain tolerance threshold (applied once every 6 s). A series of 15 stimuli was then applied once a second at an intensity of 1.2 times the reflex threshold. These procedures were performed both before and after the randomized IV injection of either 0.15 mg/kg ketamine or a placebo. The R(III) reflex threshold and its recruitment curve were not significantly altered after the injection of ketamine or placebo. By contrast, the significant increases (i.e., wind-up) in both the reflex responses and the sensations of pain observed during the higher frequency stimulation were significantly reduced after the administration of ketamine, but not placebo. This method might be useful for quantifying and analyzing the wind-up phenomenon and, thus, for studying the neurophysiological and pharmacological mechanisms underlying hyperalgesia in humans. IMPLICATIONS: The wind-up phenomenon (i.e., the progressive increase of the responses induced by repetitive nociceptive stimuli) was characterized in humans by using electrophysiological recordings of the nociceptive flexion reflex. We showed that, as in animals, this phenomenon, which might represent an elementary form of the central sensitization involved in various painful syndromes, depends on the activation of N-methyl-D-aspartate receptors, because it was selectively reduced after the administration of ketamine.

Evolution of the French public's knowledge and attitudes regarding postoperative pain, cancer pain, and their treatments: two national surveys over a six-year period.

UNLABELLED: Pain management has become a notable feature of public health policy and mass media communication in France over the past few years. To assess the evolution of the knowledge and attitudes of the French population with respect to pain management and morphine use, telephone surveys using similar questionnaires were conducted in 1990 (n = 1001) and 1996 (n = 1006). The proportion of respondents who would take pain management adequacy into consideration when selecting a surgical facility increased from 52% to 81% (P < 0.001), as did the proportion who associated morphine with pain treatment (from 44% to 80%; P < 0.001) or who would not be afraid of becoming addicted to morphine after it had been prescribed for pain relief (from 26% to 69%; P < 0.001). However, the proportion of respondents who agreed that morphine can be prescribed to patients with pain increased only slightly. In 1996, 58% of the respondents believed that their knowledge had improved over the past 5 yr and associated this improvement first with television, followed by written press articles and by interaction with physicians. Increased awareness of pain management possibilities among the public may generate increased demand on health professionals to provide adequate and precise information addressing each patient's needs. IMPLICATIONS: The results of two representative surveys conducted over a 6-yr interval show significant improvements of knowledge and attitudes regarding pain and its management in the French general population. However, these results point to the need for additional specific information that should be provided through patient-physician interactions.

[Characterization of sensation disorders and neuropathic pain related to syringomyelia. A prospective study]. / Caractérisation des troubles sensitifs et des douleurs neuropathiques liés aux syringomyélies. Etude prospective.

The present prospective study aimed to perform quantitative sensory testing (QST) in patients with painful or painless syringomyelia before and after surgical treatment of their syrinx (at 3 and 9 months). Eighteen consecutive patients with cervical or dorso-lumbar syringomyelia completed the study and 9 underwent surgery. Twelve patients had central neuropathic pain (of whom 6 were followed up). Spontaneous pain and brush-evoked allodynia were assessed. Von Frey hairs, vibrameter and a thermotest device were used to determine the mechanical-, vibratory-, thermal-detection thresholds, and the mechanical and thermal pain thresholds. Results showed evidence of deficits in temperature and pain sensibility in 17 cases, often associated with deficits in vibration and touch sensitivity (11 cases). Magnetic resonance scan, including axial images, demonstrated good correlation between paramedian extension of the syrinx and the laterality of thermal deficits. Somatosensory evoked potentials (11 patients) were abnormal in 9 cases at level, and showed good correlation with deficits in vibration. The magnitude of the thermal and tactile deficit was similar between areas of spontaneous pain and adjacent non painful areas. Surgery induced a significant decrease of tactile deficits, and to a lesser extent, of thermal deficits. Effects on neuropathic pain were positive in 3 patients (total disappearance of pain) and negligible or negative in 3 patients, despite collapse of the syrinx (in 2 cases). These results confirm that QST are useful in clinical practice to quantify the clinical results of surgery in patients with syringomyelia, and allow some hypotheses about the mechanisms of neuropathic pain in these patients.

Effects of single and repeated applications of a eutectic mixture of local anaesthetics (EMLA) cream on spontaneous and evoked pain in post-herpetic neuralgia.

The analgesic effects of single and repeated applications of a eutectic mixture of local anaesthetics (EMLA) cream on both spontaneous and evoked pains were evaluated in 11 patients with post-herpetic neuralgia (PHN). Detection thresholds, pain thresholds and the responses to suprathreshold mechanical and thermal stimuli were quantitatively determined at baseline, 30 min after the first application and after a series of daily applications over six consecutive days (duration of application: 5 h/day). In the acute situation, EMLA produced an overall anaesthetic effect without significantly reducing spontaneous ongoing pain and mechanical allodynia. Repeated applications significantly reduced paroxysmal pain and both the dynamic and static subtypes of mechanical hyperalgesia. The effects on spontaneous ongoing pain were more variable. They were inversely correlated to the magnitude of the thermal deficit at baseline, and were significant only in patients with dynamic mechano-allodynia. Pathophysiological implications of these results are discussed.

Painful and painless peripheral sensory neuropathies due to HIV infection: a comparison using quantitative sensory evaluation.

In order to characterize further, sensory disorders due to HIV-induced distal symmetrical polyneuropathy (DSPN), we compared quantitative sensory testing (QST) and electrodiagnostic parameters in patients presenting with painful or painless DSPN. Forty HIV patients with DSPN were studied and compared with ten seronegative control subjects: 15 patients presented with pains (spontaneous and/or evoked) in the lower limbs and 25 patients, matched for age, sex, duration of HIV and CD4 count, had non-painful symptoms (i.e. paresthesia). QST and nerve conduction studies (NCS) were performed on the lower limbs. von Frey hairs and a thermotest device were used to determine the mechanical- and thermal-, detection and pain thresholds. The responses elicited by suprathreshold thermal and mechanical stimuli were measured on a visual analog scale (VAS), to evaluate hyperalgesia. NCS were not significantly different between the two groups of patients. Thermal and mechanical detection thresholds, as well as the thermal pain threshold were significantly, and similarly, increased in both groups of patients as compared with the normal control subjects. Responses to suprathreshold thermal stimuli were similar in patients and control subjects. In contrast, mechanical pain thresholds were significantly decreased (mechanical allodynia) and responses to suprathreshold mechanical stimuli significantly increased (mechanical hyperalgesia) in the pain, but not in the painless patients. The intensity of mechanical allodynia/hyperalgesia was correlated with the intensity of spontaneous ongoing pain. We conclude that patients with DSPN are characterized by thermal, mechanical and electrophysiological deficits, suggestive of alterations in both small and large peripheral nerve fibers. Patients with a painful neuropathy present with static mechanical allodynia/hyperalgesia, suggestive of a selective alteration in the processing of mechanoreceptive signals, which might have a significant role in the pathophysiology of spontaneous and evoked pains in these patients.

Nefopam strongly depresses the nociceptive flexion (R(III)) reflex in humans.

Nefopam hydrochloride has been commercialized as an analgesic drug in most Western European countries for 20 years. It has been shown to possess analgesic activity with a profile distinct from that of opioids or anti-inflammatory drugs. In order to define the mechanisms of action of this pharmacological agent, we studied, in a double-blind and cross-over fashion, its effects on the nociceptive flexion (R(III)) reflex and the corresponding pain sensation in ten healthy volunteers. The R(III), reflex elicited by electrical stimulation of the sural nerve was recorded from the biceps femoris. Two experiments were performed on each volunteer at an interval of 7 days. On each experimental day, four recruitment (intensity-response) curves of the R(III) reflex were constructed: before (control period) and then 30, 60 and 90 min after the intravenous injection of nefopam (20 mg) or a placebo. Nefopam induced a powerful depression of the nociceptive R(III) reflex. It increased the threshold of the reflex and decreased the slope of the recruitment curve. At the same time, it decreased the painful sensations (as measured with a visual analogue scale(VAS)) elicited by the maximum stimulus intensity. These data suggest that nefopam probably produces its analgesic action through central (spinal and/or supraspinal) mechanisms. However, complementary peripheral mechanisms cannot be excluded on the basis of the present study. In view of these results, it seems that new clinical studies will have to be undertaken to revisit this potent analgesic agent and try to limit its adverse effects (i.e. nausea, vomiting, sweating). Its fast onset of action could clearly be an advantage, notably in the treatment of post-operative pain.

[Update on the pharmacologic approach to pain]. / Actualités de la prise en charge pharmacologique de la douleur.

Acute pain can be managed favourably by the use of paracetamol, non steroidal anti-inflammatory drugs, opioids and local anaesthetics, solely or in combination. Sophisticated methods of administration such as nerve blocks or patient-controlled analgesia will improve results. Chronic pain, on the other hand, presents a more complex situation and the pharmacological approach is only one aspect of bio-psycho-social management programmes. The role of opioids in the treatment of chronic non-cancer pain has still not been clarified. Adjuvant drugs are often required.

Effects of gabapentin on the different components of peripheral and central neuropathic pain syndromes: a pilot study.

Anticonvulsants are widely used in the treatment of neuropathic pain, and are assumed to act preferentially on lancinating, shooting pain. In the present study, the effects of gabapentin, a novel anticonvulsant, were evaluated systematically on both spontaneous and evoked pain in 18 patients with peripheral nerve injuries or central lesions. Gabapentin was administered orally in gradually increasing doses up to a maximum of 2,400 mg/day. Evaluations of spontaneous ongoing and paroxysmal pain, allodynia and hyperalgesia were performed at the beginning of the study ('baseline') and 6 weeks after the steady-state dose had been reached. Quantitative sensory tests were used to measure detection and pain thresholds to mechanical and thermal stimuli and the responses to suprathreshold stimuli. Gabapentin induced a moderate and statistically significant relief of ongoing spontaneous pain and was particularly effective in reducing paroxysmal pain. A striking finding was the significant effect on brush-induced and cold allodynia. In contrast, no effects were observed on detection and pain thresholds to static mechanical and hot stimuli. Side effects were generally minor and did not interfere with everyday activities. The present study suggests that gabapentin has preferential antihyperalgesic and/or antiallodynic effects, and is equally effective in pain due to peripheral nerve injuries and central lesions.

[The epideiology of postoperative pain]. / Epidémiologie de la douleur postopératoire.

Postoperative pain, as all types of pain, is a complex phenomenon including sensory, emotional and behavioural factors. The incidence and severity of postoperative pain is very variable between patients and is rather unpredictable. Patients characteristics as well as the types of surgery and anaesthesia will be of importance. Health professionals have a major role to play for improving effectiveness of pain management as well as safety.

A case of 'pure' dynamic mechano-allodynia due to a lesion of the spinal cord: pathophysiological considerations.

We report the unusual observation of a patient who presented with the single symptom of a very intense, brush-induced allodynia (dynamic mechanical allodynia) which was strictly confined to the left C2 and C3 dermatomes. All investigations, including a cervical spinal MRI, were initially normal. The clinical picture remained stable for several months until the appearance of spontaneous pain and sensory deficits suggestive of a spinal lesion. A second MRI revealed an intraspinal lesion involving the C2-C5 segments. In accordance with other clinical and animal studies, such an observation of a 'pure' dynamic mechano-allodynia suggests that specific mechanisms underlie each component of neuropathic pain. Possible pathophysiological mechanisms are discussed in the light of recent experimental results obtained in animals.