Stefan Lautenbacher, Marburg, Germany

Fibromyalgia is a chronic pain condition with widespread pain and multiple tender points. The two pathological signs are not closely correlated in the late phases of fibromyalgia but may cause each other during the early phases of pathogenesis (Kosek et al., 1996 ; Lautenbacher et al., 1994). The tender points have appeared to be the most pain sensitive sites in extremely pain sensitive persons (Tunks et al., 1988). In other words, fibromyalgia patients suffer from a generalized form of hyperalgesia, which becomes most dramatic at the tender points. In recent studies, evidence has been accumulated that the increase in pain sensitivity is clearly most pronounced when pain was induced by mechanical stimuli but that also other physical stressors like heat and electrical current can be used to demonstrate hyperalgesia in fibromyalgia (Arroyo & Cohen, 1993 ; Kosek et al., 1996; Lautenbacher et al., 1994). The preponderance of women (60% - 80 %) amongst fibromyalgia sufferers is well known.

In summary, fibromyalgia sufferers are mainly women with an increased sensitivity to pain, which becomes most evident when experimental pain is induced by mechanical stimuli. These facts resemble those obtained when healthy women are compared to healthy men in psychophysical studies. The two sexes differ to small or moderate degrees when experimental pain is induced by thermal or electrical stimuli (Riley et al., 1998). Consequently, the occurrence of sex differences in pain sensitivity appears tentative in these cases. However, the existence of sex differences is beyond any doubt, with women appearing clearly more pain sensitive than men, when experimental pain is induced by pressure (Riley et al., 1998). Hence, it is tempting to assume that it is this tendency towards mechanical hyperalgesia, which is seen in many healthy women, that predisposes them to the more pathological forms of mechanical hyperalgesia, which is seen in many female fibromyalgia sufferers. Accordingly, it is of outstanding clinical relevance to detect the factors which make women that sensitive to pressure pain. It is conceivable that especially muscle nociceptors, which are better tested by superficial application of pressure than of heat or electrical current, show a higher sensitivity in women, which predisposes them to fibromyalgia (Sorensen et al., 1998). However, the stable sex differences might alternatively be due to the elastic properties of the female skin, which allow nociceptors to be very easily stimulated by pressure. Future studies will show whether these or other explanations help to understand the pathogenesis of fibromyalgia.

References
(1) Arroyo JF, Cohen ML. Abnormal responses to electrocutaneous stimulation in fibromyalgia. Journal of Rheumatology, 1993, 20 : 1925-1931.
(2) Kosek E, Ekholm J, Hansson P. Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms. Pain,1996, 68: 375-383.
(3) Lautenbacher S, Rollman GB, McCain GA. Multi-method assessment of experimental and clinical pain in patients with fibromyalgia. Pain, 1994, 59 : 45-53.
(4) Riley JL 3rd, Robinson ME, Wise EA, Myers CD, Fillingim RB. Sex differences in the perception of noxious experimental stimuli : a meta-analysis. Pain, 1998, 74 : 181-187.
(5) Sorensen J, Graven-Nielsen T, Henriksson KG, Bengtsson M, Arendt-Nielsen L. Hyperexcitability in fibromyalgia. Journal of Rheumatology, 1998, 25 : 152-5.
(6) Tunks E, Crook J, Norman G, Kalaher S. Tender points in fibromyalgia. Pain, 1988, 34 : 11-19.

Drugs for fibromyalgia: myth or reality?

Dr Serge PERROT. Service de Rhumatologie A et Centre de Traitement de la Douleur. Hopital Cochin, 27 Rue du Faubourg Saint Jacques, 75014 Paris, France.

Fibromyalgia is a controversial syndrome with main feature including widespread pain, painful tender points and numerous symptoms : sleep disturbance, colopathy, depression, anxiety... This syndrome seems more and more frequent, due to a better recognition by physicians but also because of increasing pressure from the media and patient associations. This leads to an increasing number of consultations and patient pain relief demands. Patients are looking for specific treatments that could decrease most of the symptoms but few valuable data are available to guide medical prescription. The use of most of drugs is based on empirical data. This situation may lead to iatrogenic risks and could give the opportunity for numerous alternative treatments not medically controlled with possible dangerous evolution. It is therefore important to list all useful but also dangerous medications and to establish prescription guidelines for drugs in fibromyalgia.
What is the situation ?
What is the patient’s demand ? Which symptoms to relieve ?
Pain is only one of the numerous symptoms of fibromyalgic syndrome. Complaints also include fatigue, sleep disturbance, depressive symptoms, colopathy... and altered quality of life. Familial, social, professionnal and sexual difficulties are frequent. Could drugs solve all the problems of the patients?
What is the physician’s position?
Most physicians do not know how to prescribe and assess efficacy of drugs in fibromyalgia. What is a failure of treatment in fibromyalgia ? The question of drug prescription raise the problem of the global management of fibromyalgia. At the beginning of the management it is mandatory to establish shared aims with the patient to assess efficacy of treatment. All these folowing items should be assessed : pain at rest or in motion, daily or sport activities, sleep quality, morning stiffness, global quality of life, anxiety, specific index of fibromyalgia (FIQ), to choose adequate treatment according to the aims, which are not the same for all patients.
How litterature analysis can guide medical prescriptions?
Controlled studies are few. Efficacy criteria vary between studies. It is not possible to conclude upon published data, that exclude negative unpublished results.
- Classical analgesics are poorly efficient in fibromyalgia. Long term treatment with NSAIDs should be avoided because of adverse effects and level 2 analgesics do not seem efficients. In practice, analgesics should be used to improve physical performances and should be prescribed before physical activity.
- Low doses of antidepressants are widely used. Tricyclic and more recent antidepressants have been assessed in numerous trials. It seems that these drugs demonstrate better efficacy than placebo at the beginning of the treatment but this efficacy does not last over long periods. These treatments could be used a s a starter of management and could act on sleep and depressive disturbance but not on pain levels.
- Muscle relaxants are also frequently used because of frequent myalgia and muscle stiffness. They should be used at low doses to avoid sedative effect that limit active participation of patients ;
- Treatment that act on muscle metabolism do not support real efficacy ; Numerous alternative treatments are proposed to patients, via classical or internet routes.
- New drugs : Growth hormon have demonstrated moderate efficacy in fibromyalgia but this treatment is expensive.
- Drugs acting on sleep disturbances : Gamma-hydroxy-butyrate, cyclobenzaprine, alprazolam have been tested in several studies, associated to analgesics or NSAIDs. Effect on sleep seem interesting but effect is weak on pain.
- Alternative treatments : Fibromyalgia is the ideal situation for the marketing of many uncontrolled substances, out of medical prescription and pharmacological rationale. Melatonin, creatinin, but also mesotherapy, acupuncture... have been tried without strong effects;
In conclusion, management of fibromyalgia should not be restricted to drug prescription, most of drugs being poorly efficient, usually badly tolerated, not significantly different from placebo. An important part of the management should include patient’s education. It is important that physician and patients establish shared objectives, according to the social, psychological and physical situation. Drugs are an important mediator of patient-physician relations that should be used knowing the limits. Fibromyalgia represents a typical situation that enhances difficulties of chronic painful patient management and demonstrates that this management should go beyond drug prescription.

References
(1) Arnold LM, Keck PE Jr, Welge JA. Antidepressant treatment of fibromyalgia. A meta-analysis and review. Psychosomatics 2000 ; 41 : 104-13.
(2) Bennett RM, Campbell S, Burckhardt C et al. A multidisciplinary approach to fibromyalgia management. J Musculoskel Med 1991 ; 8 : 21-32.
(3) Burckhardt CS, Clark SR, Benett RM. The fibromyalgia impact questionnaire : development and validation. J Rheumatol 1994 ; 21 : 714-20.
(4) Burckhardt CS, Mannerkorpi K, Hendenberg L, Bjelle A. A randomized, controlled clinical trial of education and physical training for women with fibromyalgia. J Rheumatol 1994 ; 21 : 714-720.
(5) Carette S, Bell M, Reynolds et al. Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia. A randomized, double-blind clinical trial. Arthr Rheum 1994 ; 37 : 32-40.
(6) Goldenberg DL, Felson DT, Dinerman H. A randomized controlled trial of amitriptyline and naproxen in the treatment of fibromyalgia syndrome. Arthr Rheum 1986 ; 29 : 1371-1377.
(7) Haanen HCM, Hoenderdos HTW, Van Romunde LKJ et al. Controlled trial of hypnotherapy in the treatement of refractory fibromyalgia. J Rheumatol 1991 ; 18 : 72-75.
(8) Kosek E, Ekholm J, Hansson P. Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms. Pain 1996 ; 68 : 375-383.
(9) Nicassio PM, Schoenfeld-Smith K, Radojevic V, Schuman C. Pain coping mechanisms in fibromyalgia : relationship to pain and functional outcomes. J Rheumatol 1995 ; 22 : 1552-8.
(10) Pioro-Boisset M, Esdaile JM, Ftzcharles MA. Alternative medicine use in fibromyalgia syndrome. Arthr Care Res 1996 ; 9 : 13-17.
(11) Russel IJ, Fletcher EM, Michalek JE et al. Treatment of primary fibrosistis/fibromyalgia syndroem with ibuprofen and alprazolam. A double-blind, placebo-controlled study. Arthr Rheum 1991 ; 34 : 552-560.
(12) White KP, Harth M. An analytical review of 24 controlled clinical trials for fibromyalgia syndrome (FMS). Pain 1996 ; 64 : 211-219.

Muscular hyperalgesia: experimental and clinical evidence

Lars Arendt-Nielsen, Center for Sensory-Motor Interaction, Laboratory for Experimental Pain Research, Aalborg University, Fredrik Bajers Vej 7, D3, DK-9220 Aalborg, Denmark. LAN@smi. auc. dk.

Pain originating from deep somatic structures represents a major part of pain complaints in patients. Deep pain is a major clinical problem, and a further insight into the peripheral and central mechanisms is necessary to improve therapy. The study of referred pain from and hyperalgesia in muscles may help to uncover such mechanisms. Paradoxically, a large amount of the research in experimental and clinical pain has been obtained from studies on cutaneous pain. Cutaneous pain varies in many ways from deep pain. It is typically described as a localised sharp or burning pain and is rarely (if ever) referred to other structures. On the contrary, deep pain is often described as a diffuse, dull pain usually referred to distant sites. Referred muscle pain (and the possible related hyperalgesia) is manifested in somatic structures (skin, muscles, joints, tendons). These manifestations are of significant clinical importance for the diagnosis of pain pathologies.
Further basic research into all aspects of referred pain and hyperalgesia related to deep tissue is needed. Clinical pain research is often confounded by many factors, which make it difficult to look at certain aspects of the disease. Experimental models, which can be standardised by using healthy subjects, are useful in basic research, because they allow a study without confounding factors.
Human experimental pain research involves two separate topics : Standardised activation of the nociceptive system and measurements of the evoked responses. The ultimate goal of advanced human experimental pain research is to obtain a better understanding of mechanisms involved in pain transduction, transmission, and perception under normal and pathophysiological conditions. Hopefully, this can provide better characterisation, prevention, and management of pain and give more insight into the mechanisms underlying referred pain and deep tissue hyperalgesia.
In experimental pain research on muscle hyperalgesia and referred pain we have the possibility to control stimulus intensity, duration, and modality. Furthermore, the psychophysical evoked responses can be assessed quantitatively (using for example visual analogue scores) or qualitatively (using for example McGill Pain Questionnaire). Stimulus-response relationships, being of great value in for example pharmacological research, can also be investigated. Disadvantages of experimental models are the short lasting acute stimuli, which may not parallel clinical pain, typically being of a longer duration. One-dimensional (a single modality) experimental pain stimuli may be inadequate in for example assessing pharmacological interventions on muscle hyperalgesia and under such circumstances ; the most reliable experimental test situations should probably rely on multi-dimensional testing using different experimental pain stimuli. Using different stimulus modalities it is possible to tease out the mechanisms involved. This multimodal sensory test regime should also be employed when hyper-/hypoalgesia is assessed in muscles and in related referred pain areas.
Many painful conditions, others than neurogenic pain, may involve neuroplastic changes within the central nervous system. Little attention has been paid to the fact that e. g. chronic musculoskeletal pain disorders may generate neuroplastic changes. It seems evident this may happens as conventional pain management regimes do not sufficiently modulate many painful disorders involving deep structures. Basic animal studies have provided evidence to support the notion that nociceptive activity from deep structures are more potent to generate central neuroplastic changes. We have performed two lines of research involving pain form deep structures : Experimental painful stimulation of muscle in 1) healthy volunteers and in 2) chronic pain patients. Muscle pain was induced by hypertonic saline, various algogenic substances (bradykinin, serotonin, substance P) and by intramuscular electrical stimulation (temporal summation to repeated stimuli). The algogenic substances can generate transient muscular hyperalgesia in healthy volunteers. In patients with chronic musculoskeletal pain (whiplash, fibromyalgia, osteoarthritis) experimental induction of muscle pain generate significantly more pain and larger referred areas compared with controls.
The somatosensory sensibility in the referred pain area may give additional information about the mechanisms involved in generation of referred pain. In general, it is accepted that muscle pain can result in hyperalgesia in the referred somatic structures. Interestingly, modality specific changes have been observed in referred areas including as well hypo- as hyperalgesia.
Central hyperexcitability of dorsal horn neurones caused by the muscle pain may explain the expansion of pain with referral to other areas and probably also hyperalgesia in these areas. However, facilitated neurones cannot account for hypoalgesia to certain sensory stimuli in the referred area. Descending inhibitory control of the dorsal horn neurones may explain the decreased response to additional noxious stimuli in the referred pain area. Recently, we found that saline-induced muscle pain gave reason to deep tissue hypoalgesia in extra segmental areas (including the area of referred pain) distant from the pain focus. Alternatively, segmental inhibition may contribute to the decreased sensibility.
It seems that the manifestation of central hyperalgesia in muscle pain conditions involving referred pain share some common features with secondary hyperalgesia related to cutaneous injury :
1. The size of referred pain is related to the intensity and duration of ongoing/evoked pain.
2. Temporal summation is a potent mechanism for generation of referred muscle and is facilitated in case of chronic musculoskeletal pain
3. Central hyperexcitability is important for the extent and hence area of referred pain.
4. Patients with chronic musculoskeletal pains have enlarged referred pain areas to experimental stimuli. Proximal spread of referred muscle pain is only seen in patients with chronic musculoskeletal pain.
5. Modality specific somatosensory changes occur in referred areas emphasising the importance of using a multimodal sensory test regime.
Human experimental pain research has provided new possibilities to study referred pain quantitatively in volunteers and patients. Clinical studies and pharmacological modulation of experimentally induced referred pain may contribute with additional information concerning the underlying mechanisms. Better characterisation and understanding of referred pain mechanisms and related muscle hyperalgesia may help to optimise and rationalise pain management.

References
Arendt-Nielsen L., Induction and assessment of experimental pain from human skin, muscle and viscera. In : T. S. Jensen, J. A. Turner, and Z. Wiesenfeld-Hallin (Eds. ), Proceedings of the 8th World Congress on Pain. IASP press, Seattle, 1997, pp. 393-425.
Arendt-Nielsen L., Graven-Nielsen T., Svensson P., Jensen T. S. Temporal summation in muscles and referred pain areas : an experimental human study, Muscle Nerve, 20 (1997) 1311-1313.
Babenko V., Graven-Nielsen T., Svensson P., Drewes A. M., Jensen T. S., Arendt-Nielsen L., Experimental human muscle pain and muscular hyperalgesia induced by combinations of serotonin and Bradykinin. Pain, 82 (1999) 1-8.
Babenko V., Graven-Nielsen T., Svensson P., Drewes A. M., Jensen T. S., Arendt-Nielsen L., Experimental human muscle pain induced by intramuscular injections of bradykinin, serotonin, and substance P. Eur. J. Pain, 3 (1999) 93-102.
Giamberardino MA, Rampin O, Laplace JP, Vecchiet L, Albe-Fessard D. Muscular hyperalgesia and hypoalgesia after stimulation of the ureter in rats. Neurosci Lett. 1988 ; 87 : 29-34.
Giamberardino MA, Berkely KJ, Iezzi S, De Bigontina P, Vecchiet L. Pain threshold variations in somatic wall tissues as a function of menstrual cycle, segmental site and tissue depth in non-dysmenorreic women, dysmenorreic women and men. Pain, 71 (1997) 187-97.
Graven-Nielsen T., Arendt-Nielsen L., Svensson, P. Jensen T. S. Experimentel muscle pain : A quantitative study of local and referred pain in humans following injection of hypertonic saline, J. Musculoskel. Pain., 5 (1997) 49-69.
Graven-Nielsen T., Arendt-Nielsen L., Svensson P., Jensen T. S., Quantification of local and referred muscle pain in humans after sequential i. m. injections of hypertonic saline, Pain, 69 (1997) 111-117.
Graven-Nielsen T., Babenko V., Svensson P. Arendt-Nielsen L. Experimentally induced muscle pain induces hypoalgesia in heterotopic deep tissues, but not in homotopic deep tissues, Brain Res., 787 (1998) 203-210.
Hockaday J. M., Whitty C. W. Patterns of referred pain in the normal subject, Brain, 90 (1967) 481-496.
Hoheisel U., Mense S. Long-term changes in discharge behaviour of cat dorsal horn neurones following noxious stimulation of deep tissues, Pain, 36 (1989) 239-247.
Hoheisel U., Mense S. Response behaviour of cat dorsal horn neurones receiving input from skeletal muscle and other deep somatic tissues, J. Physiol. (Lond. ), 426 (1990) 265-280.
Hoheisel U., Mense S., Simons D. G., Yu,X. M. Appearance of new receptive fields in rat dorsal horn neurons following noxious stimulation of skeletal muscle : a model for referral of muscle pain?, Neurosci. Lett., 153 (1993) 9-12.
Hoheisel U., Mense S., Ratkai M. Effects of spinal cord superfusion with substance P on the excitability of rat dorsal horn neurons processing input from deep tissues, J. Musculoskel. Pain., 3 (1995) 23-44.
Hu J. W., Sessle B. J., Raboisson P., Dallel R., Woda A. Stimulation of craniofacial muscle afferents induces prolonged facilitatory effects in trigeminal nociceptive brain-stem neurones, Pain, 48 (1992) 53-60.
Inman V. T., Saunders J. B. C. M. . Referred pain from skeletal structures, J. Nerv. Ment. Dis., 99 (1944) 660-667.
Koelbaek Johansen M., Graven Nielsen T., Schou Olesen A, Arendt-Nielsen L. Generalised muscular hyperalgesia in chronic whiplash syndrome. Pain, 83 : 2 (1999) 229-34 Kellgren J. H., Observation on referred pain arising from muscle, Clin. Sci., 3 (1938) 175-190.
Laursen R J., Graven-Nielsen, T., Jensen, TS., Arendt-Nielsen, L. The effect of compression and regional anaesthetic block on referred pain intensity in humans. Pain, 80 (1999) 257-263.
Marchettini P., Simone D. A., Caputi G., Ochoa J. L. Pain from excitation of identified muscle nociceptors in humans, Brain Res., 740 (1996) 109-116.
Mense S. Nociception from skeletal muscle in relation to clinical muscle pain, Pain, 54 (1993) 241-289. Mense S. Referral of muscle pain, APS. J., 3 (1994) 1-9.
Svensson P. , Arendt-Nielsen L., Nielsen H., Larsen J. K. Effect of chronic and experimental jaw muscle pain on pain-pressure thresholds and stimulus-response curves. J. Orofacial Pain, 9 (1995) 347-356.
Sorensen J., Graven-Nielsen T., Henriksson K. G., Bengtsson M., Arendt-Nielsen L. Hyperexcitability in fibromyalgia, J. Rheumatol., 25 (1998) 152-155.
Torebjork H. E., Ochoa J. L., Schady W. Referred pain from intraneural stimulation of muscle fascicles in the median nerve, Pain, 18 (1984) 145-156.
Vecchiet L., Galletti R., Giamberardino M. A., Dragani L., Marini F. Modifications of cutaneous, subcutaneous, and muscular sensory and pain thresholds after the induction of an experimental focus in the skeletal muscle, Clin. J. Pain, 4 (1988) 55-59.

Musculo-skeletal and facial pain: new concepts in mechanisms

Barry J. Sessle, Faculty of Dentistry, University of Toronto, Toronto, Canada M5G 1G6

Small-diameter nociceptive afferents supplying musculoskeletal tissues or other tissues in the craniofacial region project to the trigeminal (V) brainstem sensory nuclear complex. Many neurones in the V brainstem complex respond to craniofacial nociceptive afferent inputs; these nociceptive neurones have been categorized as either nociceptive-specific (NS) neurones or wide dynamic range (WDR) neurones. Some of these neurones have projections to other brainstem regions and thereby may contribute to the central substrate underlying autonomic and muscle reflex responses to craniofacial stimuli. Many project to higher levels of the brain and may participate in the sensory-discriminative, affective and other dimensions of pain.
Some of the V brainstem NS and WDR neurones respond exclusively to cutaneous sensory inputs and have features suggesting they are critical neural elements involved in our ability to localize an acute superficial craniofacial pain and sense its intensity and duration. Many of the V brainstem nociceptive neurones, however, receive convergent inputs from afferents supplying other craniofacial tissues (e. g. muscle) as well as skin. These neurones are likely involved in deep pain, since few nociceptive neurones exclusively receive inputs from afferents supplying these tissues ; indeed, the extensive convergent input patterns that they show suggest their involvement also in pain spread and referral that is typically seen in several craniofacial pain conditions involving deep tissues. Convergence is also thought to be an important factor underlying the neuroplastic changes in V neuronal properties that may occur with peripheral injury or inflammation. For example, application of the small-fibre excitant and inflammatory irritant mustard oil to the temporomandibular joint or muscle induces a prolonged but reversible enhancement of the cutaneous as well as deep afferent inputs to most NS and WDR neurones and expansion of their cutaneous or deep mechanoreceptive field. Noxious stimulation of musculoskeletal tissues is much more effective than cutaneous stimulation in inducing these neuronal changes that involve a number of neurochemical mechanisms, including excitatory amino acids acting through NMDA receptors. Several inhibitory neuromodulatory processes have also been revealed, and these include processes utilizing GABA and endogenous opioids such as the enkephalins. These central neuroplastic changes may be accompanied by increased EMG activity reflexly induced in the masticatory musculature, and are thought to reflect a central sensitizationof V nociceptive neurones. They are manifested in nociceptive neurones in the rostral as well as caudal components of the V brainstem complex, and the central sensitization of rostral V neurones appears dependent upon the neuroplastic changes induced in caudal components of the V brainstem complex. The changes in brainstem nociceptive neuronal properties reflect the functional plasticity of the central V nociceptive system, and may be involved in the development of conditions that manifest deep craniofacial pain.
There is recent evidence that several of the centrally acting neurochemicals noted above also have actions in peripheral tissues and may contribute to processes that modify the phenomenon of peripheral sensitization. This phenomenon reflects in part an increased excitability of peripheral nociceptive primary afferents and is a frequent accompaniment of injury and inflammation. The primary afferent cell body is another potential site of alterations induced by certain types of injury. In the case of mechanisms operating at the peripheral endings of nociceptive afferents, data from animal models of craniofacial pain and inflammation reveal that the central consequences of peripheral nociceptive afferent inputs into the brainstem may be modulated by the local (e. g. temporomandibular joint) application of excitatory amino acid receptor agonists and antagonists, opiates, and GABA. These locally acting chemicals may modulate peripheral sensitization and the excitability of peripheral nociceptive afferents. Sex differences have been documented in some of these processes and may be related to the male/female differences in the prevalence of a number of craniofacial pain conditions. Furthermore, the findings that a number of centrally acting neurochemicals also have actions in peripheral tissues offer the prospect of new therapeutic approaches to manage pain through local application of pharmacological agents.

References
Sessle, B. J. The neural basis of temporomandibular joint and masticatory muscle pain. J. Orofacial Pain 4 : 238-245, 1999.
Sessle, B. J. Acute and chronic craniofacial pain : brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit. Rev. Oral Biol. Med. 11 : 57-91, 2000.

Musculoskeletal and facial pain: new concepts in taxonomy

A. Woda

Several types of head and neck pain have recently been grouped in the new taxonomic concept of idiopathic orofacial pain 1,2 . Usually these pain entities are split into four or five different groups. This classification is based upon the type of tissue affected: mucosa for stomatodynia, bone for atypical facial pain, teeth for atypical odontalgia, muscle for myofascial pain and the temporomandibular joint for capsular and disc disorders. Recently, the priority given to anatomical criteria in the current pain classification systems 3,4,5 has been questioned 6 because this may separate pain entities that share common clinical features and/or mechanisms purely on an organ or tissue basis. Indeed these illnesses display many common features 7 . They are restricted to tissues or organs of the face or oral cavity, or tissues directly related to them, such as the temporomandibular joints and the muscles of mastication. They do not not follow a nervous pathway. In all cases, the pain is continuous, is present throughout all or part of the day and is absent or infrequent during sleep. The pain has been present for at least the previous four months or has returned periodically in the same form over a period of several months or years. Although pain may be recurrent, it has no paroxysmal character. All researchers have noted a strong female predominance. There is a higher prevalence of psychosocial disturbance in these patients than in the general population. Certain personality traits, difficult social circumstances (family problems, problems at work, or sociocultural disharmony), or psychological problems (depression, anxiety, continuous or episodic emotional instability) are often reported in direct association with the illness. Based on clinical, radiographic or laboratory examination, none of the idiopathic orofacial pain entities stated above have an obvious detectable organic cause, and accordingly the pain is the main if not the only motive for consultation. Partly validated diagnostic criteria are available for the different subgroups of masticatory and TMJ disorders 5,8 . No validated criteria have been proposed for the whole group and for other types of idiopathic orofacial pain. The description of pain found in the literature does, however, allow diagnostic criteria common for the whole group of idiopathic orofacial pain to be proposed.
In addition to their shared clinical characteristics, there are several other good reasons for grouping these different disorders. They commonly occur simultaneously or consecutively 1 in the same patient. Also, the treatment of all these disorders is often non-specific, and the reasons for success or failure of treatment are poorly understood. As the term “idiopathic” indicates, the aetiology and physiopathology of these illnesses are unknown but the many different hypotheses that have been proposed to explain their physiopathology are for the most part common.
Trauma, hormonal, psychological and local irritation are the aetiologic or risk factors most commonly cited. The role of trauma, for example, is evoked because of the frequent traumatic onset of pain. The role of female hormones is suggested by a strong female prevalence, and by the effects of physiological and therapeutic modification of oestrogen levels in sufferers. Chronic dental, or other orofacial irritation or inflammation may induce peripheral sensitisation. Section of the apical nerve during pulpectomy or tooth avulsion as well as many other surgical or traumatic events may be the cause of ectopic activities that may induce chronic pain. The presence of psychosocial factors is also a frequent feature of these pain states and has to be considered in the possible factors, but it is not known whether these are causal or whether it is the pain that induces the psychosocial problem. However, none of the above can currently be considered as the sole aetiology but these different factors may trigger changes in peripheral nerves and/or the central nervous system.
Peripheral changes may also induce, in the brain stem trigeminal nociceptive neurones, a central sensitisation which appears to be a key mechanism in many of these idiopathic orofacial pain conditions. Central sensitisation can be initiated and/or maintained by ectopic impulses which could be induced by a traumatic event damaging peripheral nerves. It could also be induced by ongoing peripheral afferent activity linked to a hormonal, metabolic or degenerative disruption of sensory receptors in the peripheral tissues or in the nerve fibres. As inferred from certain clinical features and therapeutic responses in both atypical facial pain and atypical odontalgia, the sympathetic nervous system might also participate in the maintenance of central sensitisation. The loss of segmental inhibitory control is another possible mechanism. It could result from deafferentation following nerve injury but also from impairment or loss of inhibitory interneurones. If psychosocial factors do exist, their physiopathology could be based, at least in part, on central sensitisation maintained by net descending excitatory controls from the brain on trigeminal nociceptive neurones 9 . Finally, it can be suggested that the different physiopathological mechanisms may act indifferently on each of the different target tissues and that in many cases these various mechanisms may be associated.

References
(1) Feinmann C. Idiopathic orofacial pain : a multidisciplinary problem : the contribution of psychiatry and medicine to diagnosis and management. In : Campbell JN (ed). Pain - An updated review. Seattle : IASP press, 1996 : 397-402.
(2) Harris M. Idiopathic orofacial pain : Idiopathic facial pain. In : Campbell JN (ed). Pain - An updated review. Seattle : IASP press, 1996 : 403-412.
(3) Merskey, H. and Bogduk, N. Classification of chronic pain : description of chronic pain syndromes and definitions of pain terms. second. 1994. IASP Press.
(4) Headache Classification Committee at the Internatiional Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgia, and facial pain. Cephalgia 1988 ; 8 : 1-96.
(5) Okeson, J. P. Orofacial Pain : guidelines for assessment, classification, and management. 1996. Quintessence Publishing Co.
(6) Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, Lipton R, Loeser JD, Payne R, Torebjork E. Towards a mechanism-based classification of pain ? Pain 1998 ; 77 : 227-229.
(7) Woda A., Pionchon P. Focus article : A unified concept of idiopathic orofacial pain : clinical features. J. Orofacial Pain 13 : 172-184, 1999.
(8) Dworkin SF, LeResche L. Research diagnostic criteria for temporomandibular disorders : Review, criteria, examinations and specifications, critique. J Craniomandib Pract 1992 ; 6 : 301-355.
(9) Ren K., Dubner R. Focus article : Central Nervous system plasticity and persistent pain. J. Orofacial Pain 13 : 155-163, 1999.

Musculoskeletal and facial pain. New concepts in the clinical management

Prof. Dr. Sandro Palla, Department of Masticatory Disorders, Center for Dental and Oral Medicine and Maxillofacial Surgery Plattenstr. 11CH-8032 Zurich, Switzerland

Muskuloskeletal pain represents, together with atypical facial pain, atypical odontalgia and the burning mouth syndrome or stomatodynia, not only a form of idiopathic facial pain but it is also the most often cause of this pain condition : up to two thirds of patients with facial pain or headache may suffer from this pain condition(3).
Like for the three other conditions the etiopathology is poorly understood ; an exception is the arthrogeneous pain for which the pathogenesis is well known. Moreover, its diagnosis is not always very simple because the symptomatology is not pathognomonic, patients have often a comorbidity of conditions with similar pain traits and the pain is mostly not localized to the masticatory structures but spreads to the teeth, face, neck and sometimes down to the shoulders, a phenomenon that is most likely caused by the convergence of trigeminal and non-trigeminal input on nociceptive neurons in the trigeminal brainstem complex (11)}. In the light of this complexity, differential diagnosis become mandatory for a successful treatment and in case of a muskuloskeletal problem it is necessary to differentiate between a myogeneous or an arthrogeneous problem.
In the past the only therapy for muskuloskeletal pain was an occlusal treatment as it was thought that its etiology was related to an occlusal disturbance. Today, it is well recognized that occlusal disturbances play only a secondary role, if any, in the etiology of muskuloskeletal pain (7, 9). In addition it has been largely acknowledged that this condition shares common features with other muskuloskeletal pain conditions. Therefore, the treatment follows the same rules as for muskuloskeletal pain in general.
It is necessary to distinguish between the management of an early/acute or chronic condition as in the vast majority of cases muskuloskeletal pain is self-limiting and does not progress to cronicity. Furthermore, most patients with chronic muskuloskeletal pain seem to cope adequately and therefore keep adequate levels of psychosocial function. Only a small segment of these chronic patients are unable to cope well and demonstrate higher rates of depression, somatization and health care use, though they do not differ as far as the somatic disorder is concerned from the other coping patients (5).
Early management
The treatment goals are to eliminate/decrease pain, reduce loading of the masticatory structures, to improve/restore movements and oral function and above all to inform the patient that the condition is benign. The analgesic goal aims to avoid the development of a chronic pain state by eliminating the nociceptive inputs by means of non-invasive treatment modalities : counseling, pharmacotherapy (analgesic or antiinflammatory drugs) and physical therapy (8). Under the assumption that at least at the beginning the muscle pain may be caused by muscle overloading, caused by prolonged and/or repetitive muscle work, as it has been reported for occupational muscle pain disorders (12), the patient should learn to avoid bruxism and to keep the mandible in a physiological postural position. As far as pharmacotherapy, it is important to remember that anti-inflammatory drugs are indicated only in case of an inflammation, which is not the case of the pain of muscle origin or for most cases of ostheoarthrosis because most often this condition is inactive i.e. it is not accompanied by a synovitis. Caution is therefore indicated in the prescription of non-steroidal anti-inflammatory drugs because of their toxic effects and the lack of evidence for their efficacy in the treatment of masticatory myalgia (1, 2).
The majority of patients with muskuloskeletal pain benefit from physical therapy for home care or professionally provided (heat/cold application, massage, and exercises designed to increase functional activity), though its long time therapeutic effect has never been proven (6). Nevertheless, physical therapy is a good, non-invasive approach to actively involve the patient in the treatment plan and to make him/her feel responsible for the recovery.
In addition, the insertion of an interocclusal appliance my be indicated both in case of myogeneous or arthrogeneous pain, but this treatment modality should never be the first choice.
Management of chronic muskuloskeletal pain
As for other chronic conditions the therapeutic goal is not anymore to cure the disease/disorder but to encourage the patient to learn appropriate coping strategies intending to improve the degree of daily activity and self-responsability. Pain rehabilitation becomes an integrated process that addresses pain management and treats the physical, psychosocial, emotional and behavioral aspects secondary to the chronic pain. The management of these patients needs therefore an approach based on the biopsychosocial model of disease (4, 10). Such management requires therefore an adequate pharmacological, psychological/behavioral therapy as relaxation exercises, cognitive-behavioral treatment. The drugs used are not anymore the analgesic or antiinflammatory ones but those that act centrally to increase pain inhibition as for instance the tricyclic antidepressants or other drugs that inhibit the reuptake of both serotonin and norepinephrine (1, 2). However, it must be underlined that these drugs are not equally effective in every patient and that they do not eliminate pain but only reduce its intensity. It is to hope that in the future new, more specific drugs acting directly on nociceptive receptors will be available to treat chronic pain in a more dependable and better manner.

References
(1) Dionne RA. Pharmacological treatments for temporomandibular disorders. In : Sessle BJ, Bryant PS, Dionne RA (eds). Temporomandibular disorders and related conditions. Seattle : IASP Press, 1995 ; 363-374.
(2) Dionne RA. Pharmacologic treatments for temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997 ; 83 : 134-142.
(3) Drechsel U, Gerbershagen HU. Gesichts- und Kopfschmerzen aus der Sicht des Schmerztherapeuten. In : Siebert GK (ed). Gesichts- und Kopfschmerzen. Ein interdisziplinarer Uberblick fur Mediziner, Zahnmediziner und Psychologen. Munchen : Carl Hanser Verlag, 1992 ; 171-209.
(4) Dworkin SF. The case for incorporating biobehavioral treatment into TMD management. J Am Dent Assoc 1996 ; 127 : 1607-1610.
(5) Dworkin SF, Massoth DL. Temporomandibular disorders and chronic pain : disease or illness? J Prosthet Dent 1994 ; 72 : 29-38.
(6) Feine JS, Lund JP. An assessment of the efficacy of physical therapy and physical modalities for the control of chronic musculoskeletal pain. Pain 1997 ; 71 : 5-23.
(7) O. Orofacial pain. Guidelines for assessment, diagnosis, and management. Okeson JP (ed). Cicago : Quintessence, 1996 ; 113-184.
(8) Palla S. Therapeutic Approach to Muscle Pain in Patients with Myoarthropathies of the Masticatory System. Vecchiet L, Giamberardino MA (eds). Binghamton, USA : Haworth Medical Press, 1999 ; 1-338.
(9) Pullinger AG, Seligman DA, Gornbein JA. A multiple logistic regression analysis of the risk and relative odds of temporomandibular disorders as a function of common occlusal features. J Dent Res 1993 ; 72 : 968-979.
(10) Rudy TE, Turk DC. Integrating behavioral and dental treatments : utility of customizing protocols. In : Sessle BJ, Bryant PS, Dionne RA (eds). Temporomandibular disorders and related pain conditions. Seattle : IASP Press, 1995 ; 351-362.
(11) Sessle BJ. Acute and chronic craniofacial pain : brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit Rev Oral Biol Med 2000 ; 11 : 57-91.
(12) Simons DG, Mense S. Understanding and measurement of muscle tone as related to clinical muscle pain. Pain 1998 ; 75 : 1-17.

Central nervous system mechanisms in pain experience of fibromyalgia

(Topical seminar) Eva Kosek, MD., PhD.

The notion of tibromyalgia (FM) as a disorder of pain modulation or as a pain amplification syndrome was proposed by Smythe (1979) based on observations of widely distributed tenderness, not restricted to muscle. The experimental support for this hypothesis came later from reports of decreased pressure pain thresholds not restricted to specific muskuloskeletal locations (i. e., tender points) in FM patients. In fact, the results from several studies suggested that FM patients had a generalised increase in pressure pain sensitivity and that tender points were merely sites normally more sensitive to pressure pain in all individuals. Central nervous system (CNS) mechanisms were further supported by findings of increased sensitivity also to cutaneous heat-and cold pain stimuli in FM patients (Kosek et al. 1996a), since no cutaneous pathology has been documented in FM. Recently, perceived quality and intensity of randomised cold stimuli were assessed in painful areas in FM patients. Paradoxical heat and dysesthetic perceptions, as well as cold allodynia/hyperalgesia appeared for cold stimulation's in the painful areas of FM patients, but not in corresponding body areas in healthy controls (Berglund et al. 1999). A comparable sensation can be evoked in healthy subjects by touching warm and cool bars that are spatially interlaced, leading to reduced activity in specific cold sensitive cells thus shifting the relative pattern of activity in favour of multimodal cells that receive input from cold-sensitive C polymodal nociceptors (Craig et al. 1996). The authors proposed the hypothesis that activity in cold specific neurones normally inhibits cold evoked activity in the multimodal cells in the medial lamina I pathway to the anterior cingulate cortex (ACC). The sensitivity to innocuous thermal stimuli has been shown to be normal in FM patients (Kosek et al. 1996a), however, the relative pattern of activity could be shifted in favour of the multimodal, medial pathway to the ACC by sensitisation/disinhibition of this pathway at any level in the neuroaxis. The ACC has been implicated in the affective component of pain perception and has recently been shown to encode the perceived unpleasantness of painful stimuli in humans. Intramuscular painful stimulation is normally perceived as more unpleasant than cutaneous painful stimulation, even when the pain intensities are the same (Svensson et al. 1997a). Accordingly, the activation of ACC was reported to be more pronounced during intramuscular compared to cutaneous stimulation in healthy human subjects (Svensson et al. 1997b). The pain in FM is mainly localised to muscles (Jacobsen et al. 1993) and the increased pressure pain sensitivity is localised deep to the skin (Kosek et al. 1995). Recently, suprathreshold pressure pain stimuli have been reported to activate ACC in FM patients, but not in healthy controls (Bradley et al. 1999), which would be consistent with a relative hyperexcitability in the medial-pain pathway leading to ACC in FM patients. However, it is not known whether this would be due to sensitisation caused by increased nociceptive input from muscles and other peripheral tissues and/or disinhibition/facilitation due to a primary disorder of pain modulation.
Studies directly addressing the function of endogenous pain modulatory mechanisms in FM show no abnormalities in modulation of somatosensory perception by conditioning stimulation of large myelinated fibers, whereas a lack of normal inhibition of pain sensitivity during heterotopic noxious conditioning stimulation, suggesting a dysfunction of diffuse noxious inhibitory controls (DNIC) has been found (Kosek and Hansson 1997). There is evidence that regulation of symphathetic and cardiovascular activity is functionally linked to endogenous pain modulation. A decreased sympathetic response to a cold pressor test as well as diminished response to exercise by the symphathetic nervous system, i. e., reduced exercise induced release of serum catecholamines and reduced increase in heart rate has been reported in FM patients. The latter could contribute to the increased ischemia reported in the painful muscles of FM patients. Thus, the exacerbation of pain and tenderness typically reported by FM patients during and following physical activity (Jacobsson et al. 1993) and the lack of normal modulation of pressure pain sensitivity during isometric contraction (Kosek et al. 1996b) could result from a combination of peripheral mechanisms (i. e., sensitisation of mechanonociceptors due to muscle ischemia) and central mechanisms (i. e., dysfunction of endogenous pain modulation).
CNS mechanisms have also been implicated in FM based on changes in concentrations of transmitter substances. Low levels of the serotonin metabolite (5-HIAA) and high levels of substance P (SP) in cerebrospinal fluid (CSF) of FM patients have been reported. Serotonin has, among other actions, been associated with the inhibition of nociceptive transmission, and SP, despite possible analgesic effects, has mainly been implicated in central sensitisation. Interestingly, increased concentrations of nerve growth factor (NGF) in CSF of FM patients, but not in patients fulfilling the diagnostic criteria of FM who had a concomitant painful or inflammatory disorder, nor in patients with other chronic pain conditions than FM have been found (Giovengo et al. 1999). NGF has been implicated in the promotion of synthesis of SP. In the study of Giovengo et al. all patient groups had elevated CSF SP levels compared to healthy controls, without any statistically significant difference between the groups. This finding suggests that FM patients could constitute a heterogeneous group regarding pathophysiology, where a primary CNS disorder could be the cause of FM symptoms in one subgroup, whereas CNS changes secondary to other painful conditions could explain the FM symptoms in another subgroup.
The majority of FM patients (82%) report localised pain for several years before developing the generalised pain of FM (Burckhardt et al. 1995). Therefore, it could be speculated that in susceptible individuals, chronic localised nociceptive pain, through mechanisms such as central sensitisation and/or disinhibition spreads to involve larger parts of the body until finally widespread pain and tenderness develops. In order to investigate the possible effect of chronic nociceptive pain on somatosensory perception and endogenous pain modulation we assessed patients with painful osteoarthritis (OA) of the hip before and following surgery using the same protocol as we had previously used in our studies of FM patients. Before surgery we found sensory abnormalities in the painful area in OA patients that were in accordance with our previous findings of increased sensitivity to pressure, cold and heat pain and innocuous warmth in the maximally painful area in FM patients. No abnormalities in sensibility were found following surgery (Kosek and Ordeberg 1999). Furthermore, a lack of normal inhibition of pain sensitivity during heterotopic noxious conditioning stimulation, suggesting a dysfunction of DNIC was found before, but not following surgery in these patients (Kosek and Ordeberg 2000). The results indicate that in a healthy CNS long-term nociceptive pain can induce and maintain reversible changes in sensibility to somatosensory stimuli and in endogenous pain modulation of the same kind that have been reported in FM and have been interpreted as a sign of CNS dysfunction (Kosek et al. 1996a). Obviously, the fact that nociceptive pain can induce these abnormalities does not mean that FM patients suffer from nociceptive pain. The pain in FM (or in a subgroup of FM patients) could be caused by a primary CNS disorder affecting pain modulation, even though the total disappearance of pain in the anaesthetised part of the body in FM patients following epidural injection of lignocain exclude supraspinal mechanisms as the sole cause of pain in FM. The perceived quality of cold stimuli has to our knowledge not been studied in nociceptive pain. Therefore, it is not known if the paradoxical heat and dysesthetic perceptions of cold stimuli, that have been reported in FM and, using the same procedure, also in central post stroke pain (Berglund et al. 1999), are truly indicative of centrally induced pain conditions, and if so, could be useful in clinical diagnostic work.
Distinguishing centrally induced/maintained pain from nociceptive pain with secondary reversible central sensitisation/disinhibition constitutes a considerable challenge in scientific as well as clinical work. The development of successful strategies to accomplish this goal is crucial in order to improve our understanding of the ethiology and pathogenesis of FM.

References
Berglund, B. et al., In : P. R. Killeen and W. R. Uttal (eds. ), Fechner Day "99". Tempe, AZ : International Society for Psychophysics, 1999, pp.130-135.
Bradley, L. A. et al., 91h World Congress on Pain, Vienna, Austria, 1999, 44.
Burckhardt, C. S. et al., J. Musculoskel. Pain, 3 suppl. 1 (1995) 71.
Craig, A. D. et al.. Nature, 384 (1996) 258-260.
Giovengo, S. L., et al., J. Rheumatol., 26 (1999) 1564-1569.
Jacobsen, S. et al., Scand. J. Rheumatol., 22 (1993) 69-76.
Kosek, E. et al.. Pain, 63 (1995) 335-339.
Kosek, E. et al.. Pain, 68 (1996a) 375-383.
Kosek, E. et al.. Pain, 64 (1996b) 415-423.
Kosek, E. and Hansson, P., Pain, 70 (1997) 41-51.
Kosek E. and Ordeberg, G., Abstract, 22th Annual Meeting of Scandinavian Association for the Study of Pain, Reykjavik, Iceland, 1999 : 68.
Kosek, E. and Ordeberg, G., Pain, accepted 2000.
Smythe, H. A., Clin. Rheum. Dis., 5 (1979) 823-832.
Svensson, P. et al., Exp. Brain Res., 114 (1997a) 390-392.
Svensson, P. et al., J. Neurophysiol., 78 (1997b) 450-460.

Chronic pain and difficulties in relaxing postural muscles between repetitive maximum dynamic shoulder forward flexions: a study of patients with fibromyalgia and chronic whiplash associated disorders.

Jessica Elert, Sally Aspegren Kendall & Bjom Gerdle Department of Rehabilitation Medicine, INR, Faculty of Health Sciences, SE-581 85 Linkoping, and Pain and Rehabilitation Centre, University Hospital, SE-581 85 Linkoping, Sweden.

Aims: SAR is the ratio between muscle activity in the passive and active phases of a contraction cycle. We have previously shown that SAR is increased in patients with fibromyalgia (FM) and whiplash associated disorder (WAD) compared to pain-free controls. Moreover, among female industrial workers worsening of complaints in the neck shoulder regions correlated with high SAR one year earlier. The present study aimed to investigate if it was possible to reproduce the finding that SAR of the shoulder flexors are significantly increased in FS and WAD.
Methods: Fifty nine consecutive female patients with FM and WAD performed a shoulder forward flexion test consisting of one hundred isokinetic contractions combined with surface EMG recording. Variables investigated were;
peak torque, relative peak torque and SAR.
A randomised group of healthy pain free females served as control group.
Results: The patient groups had a higher level of tension (SAR) initially and during the endurance phase of the contractions. The patients had a lower peak torque. The three groups had similar peak torque endurance relative to initial output.
Conclusion: patients with regional and generalized pain disorders had throughout the shoulder forward flexion test a higher muscular tension level SAR than healthy pain-free controls. The present study confirmed earlier reports that patients with chronic pain have increased muscle tension during dynamic activities.
Reference: Fredin Y, Elert J et al. J Musculoskeletal Pain 1997. Lundblad I, Elert J, Gerdle B. Eur J Appi Physiol 1998.

Long-term fluctuations of pressure pain thresholds in healthy men, normally menstruating women and users of oral contraceptives

Hans Isselee, Antoon De Laat, Kris Bogaerts, Roeland Lysens. Fac.Physical Education, School of Dentistry and DeptBiostatistics, Cath. Univ. of Leuven, B-3000 Leuven, Belgium.

Aim of investigation: To evaluate wether the pressure pain threshold (PPT) in masticatory muscles of symptom-free subjects was influenced by hormonal fluctuations.
Methods: The PPT was measured with an electronic algometer during at least ten consecutive menstrual cycles in 10 women using oral contraceptives and 10 women not using oral contraceptives, with a regular menstrual cycle (26-31 days). In addition, 10 men were measured in a regular pattern over a period of one year. All subjects were symptom-free with an age range between 18 and 39 years. Measurement sessions were held during 3 different cycle phases and each session consisted of 4 consecutive PPT measurements. The PPTs of the masseter, temporalis and thumb muscles were compared between groups, hormonal phases, the 4 consecutive measurements for each muscle point per session and time by means of a linear mixed model (SAS).
Results: No significant changes of PPTs over time were found for the masseter (p=0.8419) and temporalis muscles (p=0.2786). There was no significant difference in variance for the masseter (p=0.6250), temporalis (p=0.9705) and thumb (p=0.7446) between the 3 groups. The PPTs of all muscles were significantly lower during the perimenstrual phases in the two female groups. No significant differences were found between the follicular and luteal phases.
Conclusions: The results have shown a very good consistency of the PPTs over a long time period, both in males and females. Considering the menstrual cyle as a unit, significant differences were observed during the perimenstrual days.

Results of the intravenous administration of tropisetron in fibromyalgie patients

Stratz. T., Farber L., Haus U., Miiller W.

Introduction: As described elsewhere (Stratz et al. 1994, Farber et al. 1998), the oral administration of the 5-HT3 receptor antagonist, tropisetron, at a dose of 5mg daily over 10 days leads to a significant reduction in pain, but also improves various vegetative and functional symptoms. Treatment of cytostatic-induced vomiting with intravenous 5-HT3 receptor antagonists provides quicker control of symptoms than via the oral route. This raised the question whether the amelioration of pain and improvement of other fibromyalgia symptoms wears off more quickly after intravenous treatment.
Methods: The patients were treated for five consecutive days with 2mg tropisetron i.v. bolus injection, 19 patients had experience with Tropisetron via oral route (15 responders, 4 non-responders). The efficacy parameters were: a visual analog scale (VAS) of pain; total pain score recorded on a body schematic (SSK); results of dolorimetry at 34 tender points and eight control points, changes in 17 vegetative and functional symptoms measured on a numerial scale.
Results: Patients, who had previously responded well to 10 days of oral tropisetron therapy reported that the effect of i.v. Tropisetron was more pronounced than with oral treatment, from the point of view of onset of effect and pain reduction. 3 of the former non-responders in the oral therapy responded. When the pain curve-measured by VAS-is studied for the first 14 days after beginning treatment, all patients experienced the greatest reduction in pain after the first injection of Tropisetron. However, during the following 5 days a further marked reduction in musculoskeletal pain occured. Interestingly, five-day treatment improved various vegetative and functional symptoms significantly. The treatment effect lasted mostly for several weeks.
Conclusion: A five-day injection of 2mg Tropisetron achieved a rapid and clear improvement the clinical features of approximately 70% of the patients, this suggests beginning treatment over a longer period, with i.v. administration over several days. It is not possible to predict the effect of oral treatment with tropisetron, based on the response to an initial i.v. bolus injection since i.v. bolus injection increases the response.

Patients' views on the diagnosis of fibromyalgia

C. Cedraschi, A.F. Allaz, J. Desmeules, T.L. Vischer, Divisions of Rheumatology 1, Liaison Psychiatry, Clinical Pharmacology, CH-Geneva.

The fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain condition; it is not associated with physical signs that directly relate to dysfunction; patients generally appear well, which is often in contradiction with their personal appraisal.
Aim of the investigation: to study how FMS patients view their diagnosis and the course of their illness.
Methods: semi-structured interviews were conducted with 49 patients participating in a self-management program. Content analysis of the responses was performed by 2 independent coders. Inter-coder agreement was high (=.90). Patients were mainly women (90%), with a mean age of 50 years (±7.2).
Results: duration of symptoms ranged from 1 to 38 years (mean: 7.7 years); time since diagnosis was 1 month to 13 years (mean: 2.6); time elapsed between symptom onset and diagnosis was 1 month to 36 years (mean: 5.1). The reactions to the diagnosis of FMS stressed relief and/or coping with it in 57% of the answers; no reassurance and/or negative appraisal (no cure) in 35%; lack of understanding of its meaning in 32%. Whatever the duration of symptoms, very few patients (12%) described symptom onset as gradual, without any associated event. The vast majority evoked vivid memories of somatic and/or non-somatic circumstances, with a meaningful proportion of events linked to the gynaecological-obstetrical sphere (20%) or to interventions (e.g. surgical) on the body (35%). Whatever the description of onset, pain was often (52%) described as "gaining ground", i.e. starting in one area and spreading all over as if it were an infectious disease.
Conclusion: patients' views on their diagnosis were not univocal. However, many patients stressed the importance of having been diagnosed with FMS, if for no other reason than to better cope with the contradiction between their apparent good looks and their experience of pain and suffering.
Acknowledgements: Supported by the SNSF (3200-056028.98)

Relationship between fibromyalgia and somatization

Frederique Barbot, Eric Serra, Pain Relief Unit, CHU Amiens, France

Aim of investigation: To investigate the relationship between fibromyalgia and somatization
Methods: Two groups of 30 chronic painful patients were constitued: a group of patients suffering of fibromyalgia according to the American College of Rheumatology Criteria (ACR) and a group of patients suffering of polyarthritis, painful for more than six months. Pain and somatization were evaluated in these patients: pain using analogic visual scale, body diagram and a french adaptation of the Mac Gill pain questionnary and somatization using the DSM - 3 - R criteria.
Results: Mean age in the fibromyalgia group (28 women and 2 men) is 47 years and 5 months (22 to 66). The average number of tender points is 15. In this group, the score of somatization seems to be high: 23 of the 30 patients with an average number of somatization criteria of 15. In the polyarthritis group (only 10 patients at this stage of the study: 8 women and 2 men), the average age is 43 years and 6 months (31 to 64). According to the ACR criteria, 2 women presents a fibromyalgia (tender points more than 11). 4 patients of the group presents a somatization with an average number of somatization criteria of 14.
Conclusions: First results show that polyarthritis patients can also suffer of fibromyalgia and that fibromyalgia might be a form of somatization, but fibromyalgia and somatization have similar symptoms as headhache, back pain or muscular weakness (so have polyarthritis) and might link up a process of medicalization of individual suffering.

Psychophysical indirect evidences of central pain sensitization in cyp2d6 phenotyped fibromyalgia patients

J Desmeules, C Cedraschi, V Piguef, P Dayer, TL Vischer, Clinical Pharmacology, Rheumatology, University Hospital, CH -Geneva

Nociceptive processing in fibromyalgia (FM) patients could be altered by aberrant central mechanisms. R-III nociceptive reflex, an objective physiological correlate of pain sensation, provides a tool for the evaluation of such processing as it bypasses peripheral nociceptor.
Methods: 90 FM included in an ongoing RCT of an exercise program vs 36 control (C) were assessed by R-III reflex and subjective pain thresholds monitoring after sural nerve electrical stimulation (Viking IV, Nicolet). Peripheral nociception was assessed with thermal stimuli (Thermode) and a cold pressure test. Diffuse noxious inhibitory control (DNIC) was obtained by heterotopic mechanical pressure (<4kg/cm2) of FM tender point. CYP2D6 activity was evaluated by dextromethorphan phenotyping.
Results: nearly all FM were female (98%). Age [mean 48(SEM2) vs 46(3) y.], gender and sociodemographic characteristics were similar in both groups. 73 out of 90 patients were included; main reason for exclusion was the inability to interrupt drugs with analgesic eflect for >10 days. Mean duration of symptoms was 8 y, (0.5-49). Regional Pain Score was 65(2) and pain intensity (VAS) at the time of examination was 5.6(0.3). Thermal perceptions (hot and cold) were similar in beth groups, whereas thermal pain thresholds and latency (hot, cold, and cold pressure test) were drastically decreased in FM (p<0.001). Psychophysical measures were qualitatively altered with a shift to the left and a propensity of a counterclockwise hysteresis of the response curves to electrical stimulation. R-III reflex threshold was reduced in FM [26(2) vs 36(2) mA, p<0.01]. In sharp contrast to C, DNIC was obtained in a substantial proportion of FM.
Conclusion: These observations indicate an abnormal activation of nociceptive pathways with a putative sensitization of central nervous system processing in FM. Supported by the SNSF (3200056028.98)

Long-term sufferers of pain

Siirtola, Taisto and Marjatta Musikka-Siirtola, Dept. of Neurology and Rehabilitation. Rehabilitation Centre. Tampere University Hospital, Tampere, Finland

Aim of Investigation: To study the clinical characteristics of fibromyalgia (FM) and its connection with migraine (M)..
Methods: 108 consecutive patients (94 women and 14 men) with FM were examined clinically by neurologist and neuropsychologist. FM-diagnosis was made using the ACR 1990 criteria of FM and M-diagnosis using the IHS criteria. For the purpose of differential diagnosis CT , MRI and other exa-minations were used when needed. Neuropsycho-logical tests included WAIS-R, WMS-R, DEPS, ZUNG, MSPQ .Holland and Cope.To measure the subjective pain VAS was used and SIMPI was used to assess the subjective and psychosocial aspects of pain and other symptoms of FM.
Results: Mean age of the patients was 48,2 years (SD 6,43), woman 48,7 (6,14), men 46,0 (7,19). The mean number of FM-trigger points was 16,5 (2.23), woman 16.5 (2.19), men 15,9 (2,59). All the patients had typical other symptoms of FM. Very carefully taken historia revealed that all had suffered earlier or suffered still of migraine. 52 patients had M with aura and 56 without aura. In 49 cases the close relatives had also M. Severity of FM-symptoms did not correlate with the types of M. Results of the cognitive tests did not show any remarkable findings, but DEPS showed moderate (31,5 %) or serious (15,3%) depression. VAS was between 4,0 and 10,0, mean 8,02 (SD 1.31 ).
Conclusions: Our investigation revealed all the well known characteristics of FM, but the most important finding is, that all the patients with FM are, in fact, migraineurs. When confronting and treating patients with FM we must remember, that they are long-term sufferers of pain.

Ct-guided injections of botulinum toxin type a in the treatment of myofascial and pseudoradicular pain

Matthias A.Lutze SPINE GROUP Dept. of Neurosurgery Schliiterstr. 38 D-10629 Berlin

Aim of investigation: The present prospective study aims at determining whether CT-guided intramuscular injections of botulinum toxin type A (BTX-A) enable safe and efficient relief from myofascial and cervical/lumbar pseudoradicular pain.
Methods: CT-monitoring during outpatient injection procedure permits the quick placement of the 22-G-needle tip precisely in the center of the involved muscle belly by avoiding the risk of intravascular, intrapleural or perineural application. Correct instrument positioning is checked by applying contrast medium. 21 patients (age range: 31-83 years; 10 female, 11 male) received a total of 35 injections into affected muscle groups, e.g. longissimus thoracis and iliocostalis lumborum muscles, piriformis muscle, iliopsoas muscle, trapezius and levator scapulae muscle. The standard trigger point dose was BTX-A (BOTOX®, Merz) 50-100 U in 2 mL pysiological saline with 4 mL 0.5% bupivacaine per site, maximum 3 sites.
Postinterventional physiotherapy program includes early passive stretching regimen and a subsequent active exercise period.
Results: Clinical follow-up after 1, 2, 3, 6 and 12 months post-treatment revealed lasting and marked (> 70%, visual analogue scale) pain relief and improved mobility in 72% of the patients. The quality of life was assessed as .good' to .excellent' by 67% of all patients on the basis of a multimodal outcome score 6 months after the intervention.No side effects were reported.
Conclusions: With strict indicational criteria, CT-assisted injection of BTX/A enables highly selective and safe reduction of refractory myofascial pain. Preliminary clinical results have been promising thus far.

A psychological management of fibromyalgia with combination of medical therapy and physical therapy of in-patients

Wild J., Kappel M., Stratz Th., Miiller, W.

Introduction: The treatment of fibromyalgia is unsatisfactory. About 75% of the fibromyalgia patients have psychological problems apart from pain. Therefore a psychological therapy is necessary.
Methods: 333 patients (305 women and 28 men) with fibromyalgia according to ACR-criteria where inrolled in the study. The patients received a psychological training programme: stress-coping, pain-coping, sleep-coping, coping of functional disorders and a psychological therapy (individual and in groups). In addition an individual physical therapy and drug therapy was administered. The psychological date was assessed by the german version of Beck Depression Inventory (BDI) a numeric rating skala pain (NRS-pain) and a numeric rating skala sleep (NRS-sleep), a german feeling scala from the german psychiatric v. Zerssen, at the beginning and in the end of the stay in the hospital (four weeks).
Results: The BDI was reduced from 19,71 to 14,89 (p=0,0001, Effekt size 0,74), Bf-S (feeling scala was reduced from 69,64 to 58,42 (p=0,0001, Effekt size 0,96), NRS pain was reduced from 7,78 to 6,25 (p=0,0001, Effekt size 0,73) and NRS sleep was reduced from 7,58 to 6,41 (p=0,0001, Effekt size 0,72).
Conclusion: In our opinion, the key of the success in the treatment of fibromyalgia patients is because of in the combination of psychological management, the individuell drug therapy and physical therapy. The BDI and feeling scala are suitable to reveal chances in psychological disturbances.

Loosing the control over own's life: experiences of living with fibromyalgia

Lillemor R-M. Hallberg & Ulrika Passe The Nordic School of Public Health, Box 121 33, S-402 42 Goteborg, Sweden

Aim of investigation: The aim was to describe, from the perspective of women with fibromyalgia, their experiences of living with chronic pain.
Method: The women were active members of a self-help group. In-depth interviews were conducted and transcribed verbatim. Grounded theory methodology was used in analysing the data. The aim of such a method is to generate categories and to explore the conceptual relationships between separate categories and their subcategories.
Results: A core category, describing the women's lost control over their lives, whereas pain had taken over the control. The women described repeated periods of sick-leaves due to prominent pain, leading to a vicious circle of pain, despair and decreasing quality of life. The personality of the women was characterised by over-compensatory perseverance in combination with low need for self-assertion. Despite being very ambitious, the women had always had a weak self-reliance. The women had been "good girls" which was perceived as very demanding to them. However, due to continuous performance and engagements the women acquired their self-esteem. It was obvious that the pain, at the time for the interviews, demanded a life without internal and external demands. The pain became a necessary boundary-line to them, resulting in increasing awareness of their own needs and increasing quality of life. Most women perceived the cause of fibromyalgia as biological and supported, despite not being validated, the medical doctors' seeking for the "biological fault".
Conclusions: Women with fibromyalgia use pain as a necessary boundary-line against perceived internal and external demands.

Effect on the level of pge2 and ltb4 in human masseter muscle with myalgia by intramuscular injection of glucocorticoid

Britt Hedenberg-Magnusson. Malin Emberg and Sigvard Kopp, Clinical Oral Physiology, Karolinska Institutet, 14104 Huddinge, Sweden.

Aim of investigation: To determine whether the intramuscular levels of prostaglandin E: (PGE2) and leukotriene 84 (LTB4) was influenced by local glucocorticoid administration and if changes in this level is associated with changes in pain and hyperalgesia or other clinical aspects.
Methods: Eighteen patients with fibromyalgia and seventeen with localized myalgia of the temporomandibular system were examined before and after local treatment with glucocorticoides regarding resting pain, pressure pain tolerance, maximum voluntary mouth opening and pain upon maximum voluntary mouth opening. Venous blood samples were obtained and analysed with respect to plasma concentrations of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). Three consecutive samples were obtained from the masseter muscle by microdialysis and the dialysates were analysed with respect to PGE2 and LTB4 concentration.
Results: Concentrations of PGE2 differed significantly before and after treatment on both sides side in fibromyalgia (p=0.0093 and p=0.049 respectively) as well as LTB4 on the most tender side (p=o.0015). No changes were found in the patients with localized myalgia. Concerning the clinical variables significant changes were found before and after treatment in both groups on the most tender side regarding pain upon digital palpation (p=0.005 and p=0.022 respectively), pressure pain threshold (p=0.026 and p=0.002) as well as in resting pain and pressure pain tolerance in the fibromyalgia group ( p=0.06 and p= 0.017 respectively)
Conclusion: This study shows that local glocucorticoid treatment reduces pain and hyperalgesia in painful masseter muscle and significantly decrease the levels of PGE2 and LTB4 in patients with fibromyalgia. No changes was found in localized myalgia which indicate different pathophysiology behind this condition and fibromyalgia.
Acknowledgements: Supported by the Swedish Dental association.

Tropisetron in the treatment of periarthropathies

Stratz. T.. Varga, B., Farber, L., Miiller, W.

Introduction: The disadvantage of local anaestetic is the short duration of the effect, the disadvantage of cortisone the well-known side effects. Since Tropisetron in an multicenter placebo-controlled study revealed a relief from pain in fibromyalgie the question raised wether Tropisetron caused a relief from pain not only in wide spread pain like fibromyalgia but in local pain like epicondylitis etc.
Methods: 40 patients with periarthropathies like epicondylitis or periarhtritis humeroscapularis for one week or longer were enrolled in the study. The patients must have pain under conditions of rest and load. 20 patients got lOmg Prilocain (local anaesthetic drug/Xylonest) or 2mg Tropisetron (Navoban) according to their randomisation. The study was double blinded in the way of masked observer.
Patients filled in VAS pain under conditions of rest and exercise before infiltration and three days later. In patients with periarthritis humeroscapularis Tropisetron or Prilocain was intra-articularly injected when various regions like biceps-tendon and bursa-subdeltoidea were affected.
Results: Only the group treated with Tropisetron revealed a significant relief of pain under conditions of rest (p<0.0002) and exercise (p<0.0007). A high effect size could be observered.
Conclusion: The treatment with Tropisetron in periarthropathies like epicondylitis seems to be more effective than a treatment with a local anaesthetic drug. A longer duration of effect could be observed in comparison to Prilocain. Most of the patients treated with Prilocain had only a benefit for some hours. A confirmation of these results in further studies is required in particular in comparison to cortisone.

Pain in Europe III. EFIC 2000, Nice, France, September 26-29, 2000. Abstracts book, p. 132, 134, 135, 137, 138, 148, 150, 201, 236, 238, 240, 244, 246, 249, 252, 266, 268, 275.