Effects of treatment of peripheral pain generators in fibromyalgia patients

European Journal of Pain 15 (2011) 61–69

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Effects of treatment of peripheral pain generators in fibromyalgia patients Giannapia Affaitati a, Raffaele Costantini b, Alessandra Fabrizio a, Domenico Lapenna a, Emmanuele Tafuri a, Maria Adele Giamberardino a,⇑ a b

Pathophysiology of Pain Laboratory, Ce.S.I., ‘‘G. D’Annunzio Foundation”, Department of Medicine and Science of Aging, Chieti University, Italy Institute of Surgical Pathology, Chieti University, Italy

a r t i c l e

i n f o

Article history: Received 20 February 2010 Received in revised form 18 August 2010 Accepted 5 September 2010

Keywords: Fibromyalgia Peripheral pain generators Local treatment Trigger point Joint

a b s t r a c t Fibromyalgia syndrome (FS) frequently co-occurs with regional pain disorders. This study evaluated how these disorders contribute to FS, by assessing effects of local active vs placebo treatment of muscle/joint pain sources on FS symptoms. Female patients with (1) FS + myofascial pain syndromes from trigger points (n = 68), or (2) FS + joint pain (n = 56) underwent evaluation of myofascial/joint symptoms [number/intensity of pain episodes, pressure pain thresholds at trigger/joint site, paracetamol consumption] and FS symptoms [pain intensity, pressure pain thresholds at tender points, pressure and electrical pain thresholds in skin, subcutis and muscle in a non-painful site]. Patients of both protocols were randomly assigned to two groups [34 each for (1); 28 each for (2)] to receive active or placebo local TrP or joint treatment [injection/hydroelectrophoresis] on days 1 and 4. Evaluations were repeated on days 4 and 8. After therapy, in active – but not placebo-treated groups: number and intensity of myofascial/joint episodes and paracetamol consumption decreased and pressure thresholds at trigger/joint increased (p < 0.001); FS pain intensity decreased and all thresholds increased progressively in tender points and the non-painful site (p < 0.0001). At day 8, all placebo-treated patients requested active local therapy (days 8 and 11) vs only three patients under active treatment. At a 3-week follow-up, FS pain was still lower than basis in patients not undergoing further therapy and had decreased in those undergoing active therapy from day 8 (p < 0.0001). Localized muscle/joint pains impact significantly on FS, probably through increased central sensitization by the peripheral input; their systematic identification and treatment are recommended in fibromyalgia. Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

1. Introduction Fibromyalgia syndrome (FS) is a condition of chronic widespread pain prevalent in the female sex in the adult phase of life, frequently associated with sleep disturbances, fatigue and affective dysfunction (Bennett, 2009; Sommer, 2010). According to the 1990 ACR classification criteria, it is identified by diffuse musculoskeletal pain of over 3 months duration and tenderness in at least 11 out of 18 predetermined body sites (tender points-TePs) (Wolfe et al., 1990). A typical feature of FS is a generalized increase in pain sensitivity, revealed by decreased pain thresholds to different stimulus modalities at somatic level in both painful and non-painful areas (Vecchiet et al., 1994; Carli et al., 2002; Giamberardino, 2008; Clauw, 2009). This diffuse hyperalgesia is believed to reflect a state ⇑ Corresponding author. Address: via Carlo de Tocco n. 3, 66100 Chieti, Italy. Tel./ fax: +39 0871 541207. E-mail address: [email protected] (M.A. Giamberardino).

of ‘‘central sensitization”, resulting from a complex of factors, including genetic predisposition, neuroendocrine changes and imbalance in numerous neurotransmitters, such as serotonin, dopamine, norepinephrine, substance P and nerve growth factor (Abeles et al., 2007; Buskila et al., 2007; Bradley, 2009). FS thus appears mainly rooted in the central nervous system, as a consequence its pharmacologic treatment mostly involves centrally active drugs, e.g., antidepressants or antiepileptics (Arnold, 2009). A contribution by peripheral nociceptive inputs to the syndrome is, however, being increasingly recognized (Bennett, 2005), as shown in a recent study by Staud et al. (2009), where lidocaine injection of tender points increased local pain thresholds and decreased secondary heat hyperalgesia in a remote area in FS patients, although not showing significant effects on spontaneous pain. In this view, co-morbidity of FS with other peripheral pain conditions appears crucially important; in fact, fibromyalgia patients with respect to non-FS subjects present a significantly higher frequency of numerous focal painful disorders, among

1090-3801/$36.00 Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2010.09.002

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which localized muscle pains from Myofascial Trigger Points (TrPs) – as defined by Simons’ criteria (1990) – and joint pains from microtraumas/osteoarthritis (Hong and Hsueh, 1996; Kato et al., 2006; Arnold, 2009; Ge et al., 2009a,b; Cakit et al., 2010). Input from these sources is likely to substantially contribute to the specific FS complaints, but to the best of our knowledge no systematic clinical study has so far been undertaken to verify the effects of their local treatment on fibromyalgia symptoms in standardized conditions. Based on these premises, the present study aimed at assessing the therapeutic outcome of active vs placebo treatment of myofascial TrPs or of painful joints in patients with fibromyalgia plus either myofascial pain syndromes (MPS) from TrPs or joint microtraumas/osteoarthritis. The treatment employed was local, i.e., for active therapy, anaesthetic injection of TrPs – the classic approach to MPS – and hydroelectrophoresis on painful joints, a methodology of proven efficacy in localized pain which allows in-site delivery of antalgic drugs without significant systemic effects (Brizzi et al., 2004; Graboski et al., 2005; Affaitati et al., 2006; Zaralidou et al., 2007; Scott et al., 2009). FS symptoms monitored were spontaneous diffuse pain, tenderness at TePs and hyperalgesia in a control, non-painful area. Preliminary results have already been published in abstract form (Lerza et al., 2003, 2008; Affaitati et al., 2010). 2. Methods Patients affected with fibromyalgia plus either myofascial pain syndrome (MPS) or joint pain were considered for the study, recruited from the outpatient population of the Center for the Study of Fibromyalgia of the Department of Medicine and Science of Aging, ‘‘G. D’Annunzio” University of Chieti. Normal subjects were also examined, recruited from the Health care and Nurse personnel of the same Department. The time frame of patients/subjects recruitment was 27 months. The study, subdivided into two main protocols, adhered to the guidelines established by the Helsinki declaration and was approved by the Ethic Committee of the ‘‘G. D’Annunzio” University of Chieti (no. 757/04; 01/03/04). 2.1. Fibromyalgia plus myofascial pain syndrome 2.1.1. Patients Inclusion criteria for patients of this protocol were: (a) age 18– 70 years, female sex; (b) FS diagnosed 2–5 years previously, with start of symptoms not earlier than 6 years before, average intensity of diffuse pain P50 mm of VAS and no other current therapy for FS – except low dose amitriptyline (10 mg/day) – in the preceding 3 months; (c) unilateral regional pain due to a myofascial pain syndrome from active TrPs of the upper body (diagnosis performed during the first visit) manifesting in repeated episodes (first episode 15–30 days previously, minimum number P3/week, average pain intensity P40 mm of VAS); (d) a negative clinical history for other recurrent/chronic pain conditions except FS and MPS over the past 5 years and for any medical condition known to influence general sensitivity to pain (e.g., uncontrolled hypertension, diabetes) (Obrosova, 2009; Viggiano et al., 2009); (e) informed, written consent to participate in the study. Sixty-eight women patients (aged 37–49 years) meeting all the above-described criteria were selected out of 87 examined. They had been suffering from diffuse musculoskeletal pain for 2.7– 5.8 years, diagnosed as FS 2.3–4.5 years previously. The spontaneous FS pain was perceived daily, defined as continuous with periodical exacerbations, tensive, sometimes burning, diffuse, symmetrical, experienced at muscle level in both the upper and

lower part of the body as well as along the axis. Patients also had unilateral MPS of the trapezius (1 trigger in the medial third of the upper border, thus clearly distinct from the fibromyalgia TeP in trapezius) (n = 20) or infraspinatus muscle (1 or 2 triggers) (n = 48). MPS pain was accessional; the first episode had occurred 16–19 days previously. It was described as cramping, tensive or lancinating, perceived at TrP site with radiation towards the lateral aspect of the neck, and occasionally also the retroauricular and parietal regions (trapezius) or towards the outer aspect of arm and forearm (infraspinatus) (Simons et al., 1999). 2.1.2. Study design This consisted of an 8-day main study period, with a follow-up at 30/37 days. 2.1.2.1. Main study period. At baseline (day 1) all patients underwent assessment of (1) spontaneous pain symptoms relative to the past 7 days: number of regional pain episodes from MPS and their average pain intensity (VAS scale) as well as average intensity of diffuse pain from FS; (2) pain sensitivity: pressure pain thresholds (PPTs) at trigger point site and in the 18 fibromyalgia tender points [to calculate number of positive TePs (threshold <4 kgf) and TeP score (sum of thresholds in all points)]; PPTs and pain thresholds to electrical stimulation in a neutral, non-painful area (quadriceps muscle of one side and overlying skin/subcutis). Patients were then randomly assigned to two groups of 34 each. Group A [42.9 ± 3.4 (SD) years], seven patients with trapezius TrPs and 27 with infraspinatus TrPs, received two infiltrations of their TrPs with 1-mL of 0.5% bupivacaine hydrochloride on day 1 and day 4. Group B [41.4 ± 4.2 years], 13 patients with trapezius TrPs and 21 with infraspinatus TrPs received two placebo-like injections near the trigger points on day 1 and day 4. The two groups did not differ significantly as regards mean age. At the end of the examination and therapy on day 1, all patients were given a diary to note the episodes of regional MPS pain and number of rescue medications taken for this pain (paracetamol 1000 mg, the only rescue medication allowed) for the following week. All patients were told that the protocol was designed to evaluate the effects of TrP infiltration therapy vs placebo-like infiltration therapy on consumption of this standard analgesic over the study period. They were not aware of the hypothesis in study, i.e., that TrP treatment could influence their FS symptomatology. They were also told that they would have access – or further access – to active trigger point infiltration after the first week, if needed. With this respect, a specific question was present in the diary sheet the patients were provided with, running: ‘‘based on your current local pain symptoms, do you request an additional cycle of local therapy?” [to be answered on the 8th day]. On day 4, immediately before TrP treatment, all patients reunderwent evaluation of FS symptoms, i.e. average intensity of diffuse musculoskeletal pain since day 1 and thresholds in the TePs and control area. On day 8, all measurements of day 4 were repeated. In addition, collection was performed of MPS data relative to the past week [number of MPS episodes and rescue medications taken, assessment of average MPS pain] and PPTs were also re-measured at trigger point site. After these evaluations, patients’ request for further local treatment of their trigger point was acknowledged [according to their answer to the specific question in the diary] and anaesthetic TrP infiltration was performed in all those requesting it, to be repeated after 2 days (day 11). All patients were asked to continue monitoring MPS symptoms until the follow-up visit. 2.1.2.2. Follow-up. This was planned on day 30 for all patients not requesting further infiltration therapy on day 8, and on day 37

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for patients who underwent an infiltration/further infiltration cycle starting on day 8. On this occasion, MPS data of the preceding 3 weeks were collected and average FS pain intensity relative to this same period was again measured. During the study, all patients were asked to remain on their standard dose of amitriptyline and avoid assumption of any other drug apart from paracetamol when necessary. 2.1.3. MPS/FS diagnosis Diagnosis of both syndromes was performed by an experienced clinician. Since differentiation between Myofascial Trigger Points and fibromyalgia tender points can be particularly difficult if based on local tenderness evaluation only (Tunks et al., 1995), Simons’ criteria (1990) for trigger detection were strictly followed, i.e., identification of the ‘‘taut band” in which the TrP is included and, upon TrP stimulation, elicitation of a local twitch response and reproduction of the referred pain pattern, all distinctive features of TrPs that are absent in tender points (Simons and Mense, 2003). For MPS diagnosis, palpation of muscles for TrP search was thus systematically performed in all patients and TrP assessment carried out by firstly applying pincer or snapping palpation to identify the taut band and elicit a local twitch response, and then by firm digital pressure onto different points of the band itself. The TrP within the band was revealed by a jump sign reaction by the patient towards this pressure and by the occurrence of referred in addition to local pain (Gerwin, 2001, 2005). The patient was simply invited to report the kind of sensation felt upon TrP compression and its location. No solicitation regarding the referral of pain was made by the investigator. With this procedure, one or more TrPs were identified whose compression reproduced the regional spontaneous pain complaint by the patients. When more than 1 TrP was identified, only 1 TrP, the most hyperirritable, was chosen for subsequent treatment; this occurred only in a few patients (n = 5) (Giamberardino et al., 2007; Affaitati et al., 2009). FS diagnosis had been performed either by the personnel of our Center 2–5 years previously, based on ACR criteria (Wolfe et al., 1990), or by another Center the patients had been examined at in the past. In the second case, it was verified that it had been performed according to the appropriate criteria. 2.1.4. TrP treatment 2.1.4.1. Active treatment. The infiltration was performed deeply at muscle level (Graboski et al., 2005; Zaralidou et al., 2007; Scott et al., 2009; Venancio et al., 2009). The needle tip was made to penetrate deep under the fascia and then a small amount of anaesthetic was injected first into the point. The needle was then withdrawn slightly; its inclination was changed fractionally and again a small quantity of anaesthetic was injected. The procedure was repeated six times so as to perform microinjections all around the TrP in a circular area of approximately 2 mm in diameter (Simons et al., 1999). 2.1.4.2. Placebo-like treatment. A true placebo counterpart for TrP infiltration does not exist since any TrP needle penetration, without or with fluid injection (dry needling, injection of saline, etc.) is known to produce a significant therapeutic effect (Simons and Mense, 2003; Kamanli et al., 2005; Hong, 2006). A ‘‘placebo-like” procedure was thus adopted, which proved to not produce any therapeutic effect in a previous study by this group on trigger points of the cranio-cervical area. This consisted of penetration of a needle not in the TrP site, but in a nearby area, 1 cm aside (Giamberardino et al., 2007). The study protocol was double-blind, in that neither the patients nor the clinicians collecting the data and performing the sensory evaluation were aware of the group the patients were assigned to. The clinician performing the active or placebo-like

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injection of the TrP was different from the other operators carrying out the evaluations and was the only one in the study to be unblinded as to the patients’ group. 2.2. Fibromyalgia plus joint pain 2.2.1. Patients Inclusion criteria were: (a) age 18–70 years, female sex; (b) FS diagnosed 2–5 years previously, with start of symptoms not earlier than 6 years before, average intensity of diffuse pain P50 mm of VAS and no other current therapy for FS – except amitriptyline (10 mg/day) – in the past 3 months; (c) regional joint pain in either shoulder or knee of one side, from impingement or osteoarthritis (already documented instrumentally at the first visit, and confirmed clinically during this same visit) occurring in repeated episodes (first 15–30 days previously, minimum number P3/week, average intensity P40 mm of VAS); (d) a negative clinical history for other recurrent/chronic pain conditions except FS and joint pain over the past 5 years and for any medical condition known to influence general sensitivity to pain (e.g., uncontrolled hypertension, diabetes) (Obrosova, 2009; Viggiano et al., 2009); (e) informed, written consent to participate in the study. Fifty-six women (26–66 years) meeting all the indicated criteria were selected out of 74 examined. They had been suffering from diffuse musculoskeletal pain, similar to that described by patients of protocol (1), for 2.6–4.7 years, diagnosed as FS 2–3.8 years previously. Patients were also affected with unilateral shoulder pain (from rotator cuff partial tear or tenosinovitis of the long head of the biceps tendon) (n = 34) or knee pain from osteoarthritis (n = 22) documented at ultrasounds, X-rays and/or CT-scan or MR imaging (Ardic et al., 2006; Drakos et al., 2009; Murray and Shaffer, 2009). Joint pain occurred in accesses, the first episode had been 15–27 days previously. It was often of a lancinating type, perceived at joint level with radiation towards the trapezius and deltoid regions for the shoulder and towards the lower half of the thigh and upper part of the leg for the knee. 2.2.2. Study design This was identical to protocol (1) except that: – joint instead of MPS symptoms were assessed [number and average intensity of pain episodes (diary); periarticular tenderness via PPTs (one point, that of maximal tenderness)]; – joint instead of TrP treatment was performed. On day 1, after the evaluations, patients were randomly assigned to two groups of 28 each. Group A [47.6 ± 10.5 (SD) years], 18 patients with shoulder pain and 10 with knee pain, received two local 20-min treatments of their painful joint with hydroelectrophoresis on day 1 and day 4. Group B [46.2 ± 9.4 years], 16 patients with shoulder pain and 12 with knee pain, received two placebo Hydrofor applications on the same days. The two groups did not differ significantly regarding mean age. All patients were not aware of the hypothesis under study, but were told that the protocol evaluated the effects of active vs placebo Hydrofor therapy on consumption of a standard analgesic (paracetamol, 1000 mg). They were also informed that they would have access – or further access – to active Hydrofor therapy after the first week, if needed [question in the diary, as for protocol (1)]. Throughout the study all patients were asked to remain on their standard dose of amitriptyline and avoid taking any other drug apart from paracetamol when necessary. As for protocol (1), the study design was double-blind. The clinician performing the Hydrofor application was the only one to be unblinded.

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2.2.3. Joint treatment Hydroelectrophoresis (Hydrofor) was applied (D’Africa and Sartori, 2001; Brizzi et al., 2004; Affaitati et al., 2006). During an active session, each patient received 35 mg of sodium diclofenac and 0.75 mg of betametasone in agarose gel. The gel was contained in a tube with a dispencer roll linked to the negative electrode (dispenser electrode). The positive electrode (reference), a 15.5  11 cm rectangular siliconate rubber plate, was positioned over a distant skin area, with interposed conducting gel. The electrodes were connected to a computerized current stimulator, the intensity of the delivered current was that sufficient to provoke a tingling, non-painful sensation for the whole duration of treatment. Over 20 min, the dispenser, positioned perpendicularly over the area to be treated, was constantly rolled by the operator with slow linear movements, exerting a slight pressure with the hand so as to promote progression of the fluid from the tube. For placebo treatment, Group B patients underwent Hydrofor application with exactly the same modalities as Group A, but using agarose gel deprived of active compounds (Affaitati et al., 2006). 2.3. Normal subjects Inclusion criteria for normal subjects were: (a) age 18–70 years, female sex, (b) a negative clinical history for any chronic pain condition and medical condition known to influence general pain sensitivity (e.g., fibromyalgia, uncontrolled hypertension, diabetes) and of any pain in the lower limb of one side; (c) informed, written consent to participate in the study. Twenty-five subjects [43 ± 2.23 years] meeting all the indicated criteria were selected out of 43 examined. Their mean age did not differ significantly from that of all patient groups. They underwent evaluation of PPTs and electrical pain thresholds in the quadriceps muscle of one side and overlying subcutis and skin and of PPTs in areas corresponding to TrP sites of patients in protocol 1 (12 subjects in trapezius and 13 in supraspinatus) and to joint sites of patients in protocol 2 (13 subjects in shoulder and 12 in knee).

The variation of each FS parameter during therapy was evaluated via ANOVA for repeated measures with post hoc tests. The comparison between values in patients and normal subjects (age and thresholds) was performed via 1-way ANOVA with post hoc tests. Comparisons between values at corresponding times of two different groups of patients was performed via Student’s t-test for unpaired samples. Fisher’s Exact Test was applied to compare the percentage of patients requesting further therapy in Group A and Group B at day 8. The level of significance was established at p < 0.05. 3. Results 3.1. Fibromyalgia + myofascial pain syndrome 3.1.1. Main study period 3.1.1.1. MPS symptoms. Before the start of therapy, MPS parameters did not differ significantly in Groups A and B. During the week of therapy, in Group A but not Group B number and intensity of MPS episodes significantly decreased with respect to the preceding week. PPTs at trigger point were significantly lower than normal on day 1 in both groups, testifying local hyperalgesia typical of TrPs (Vecchiet et al., 1991; Simons et al., 1999; Affaitati et al., 2009) (p < 0.001). During treatment, in Group A but not Group B, PPTs significantly increased (p < 0.0001), though remaining still significantly lower than normal (p < 0.001) (Table 1; see also Section 3.4 below). During the days 1–8 period, consumption of paracetamol was 0.20 ± 0.07 (SEM) (number of 1000 mg tablets) in Group A and 2.65 ± 0.23 in Group B. The difference between the two groups was highly significant (p < 0.0001). 3.1.1.2. FS symptoms. Before the start of therapy, FS parameters did not differ significantly in Groups A and B. During treatment, In Group A but not Group B there was a significant reduction of the intensity of spontaneous pain and of tenderness in TePs (decreased number of positive TePs, increased TePscore) (p < 0.0001) (Fig. 1).

2.4. Evaluation of pain sensitivity

2.5. Statistical analysis

3.1.1.3. Pain sensitivity in the non-painful area. In both groups, all thresholds were significantly lower than normal at day 1, testifying the typical FS diffuse hyperalgesia (Abeles et al., 2007) (see Section 3.4 below) (p < 0.001). In Group A but not Group B there was a significant increase in all thresholds during treatment (p < 0.0001) (Fig. 2). In both groups, however, all values always remained significantly lower than normal (p < 0.001). At day 8, none of Group A patients vs all Group B patients needed further TrP infiltrations, the difference in request between the two groups was highly significant (p < 0.0001). Two active TrP injections were thus performed in Group B (on that day and day 11).

Mean ± SEM were calculated for all parameters at each evaluation time in every group of patients and in normal subjects. The comparison between MPS/joint pain parameters before and after therapy was performed via Student’s t-test for paired samples.

3.1.2. Follow-up At day 30, only 4 out of 34 patients of Group A reported MPS episodes from day 8: three patients had one episode and one patient two episodes [0.15 ± 0.07, mean for the whole group],

In patients and normal subjects this consisted of measurement of PPTs via Fischer’s algometer (Fischer, 1998) and of electrical pain thresholds in skin, subcutis and muscle using a computerized constant current stimulator according to techniques already described in detail elsewhere (Giamberardino et al., 2005, 2007). Measurements were always performed in the morning (10:00 a.m.– 12:00 a.m.), with subjects lying comfortably on an examination bed in a quiet room. PPTs were measured first, followed by electrical thresholds first in skin and then in subcutis and muscle.

Table 1 MPS symptoms over 7 days before and 7 days after start of local trigger point therapy in 34 patients undergoing TrP anaesthetic infiltration (Group A) and 34 patients undergoing needle penetration in an area nearby the trigger. Mean ± SEM.

***

Type of treatment

Number of MPS pain episodes before

Number of MPS pain episodes after

Intensity of MPS pain (mm of VAS) before

Intensity of MPS pain (mm of VAS) after

PPTs at TrP site (kgf) before

PPTs at TrP site (kgf) after

Active TrP treatment (Group A) Placebo-like TrP treatment (Group B)

5.56 ± 0.32 5.29 ± 0.27

0.97 ± 0.12*** 5.56 ± 0.37 NS

62.15 ± 1.95 61.06 ± 1.79

19.15 ± 2.23*** 62.52 ± 1.60 NS

1.59 ± 0.09 1.50 ± 0.08

2.93 ± 0.04*** 1.56 ± 0.09 NS

p < 0.001, NS = not significant; comparison between before and after values.

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Fig. 1. FS symptoms. Left graph: intensity of spontaneous pain (VAS); middle graph: number of positive tender points (pressure threshold <4 kgf); right graph: tender point score (sum of pressure pain thresholds at all 18 TeP sites) in FS patients undergoing either active treatment of Myofascial Trigger Points (TrPs) (Group A, n = 34) or placebolike treatment of TrPs (Group B, n = 34) (mean ± SEM). Evaluations performed in basal conditions (day 1), on day 4 and day 8. p < 0.001. Asterisks over SEM bars refer to comparison of post-treatment (day 4 and day 8) with pre-treatment values (day 1). For Group A: p < 0.001 also between day 4 and day 8 for all measures.

always of mild intensity [15–34 mm of VAS, 2.68 ± 1.34 mean in all], not requiring any paracetamol assumption. The average FS intensity for the whole group was: mm 55.70 ± 1.29, not significantly different from values recorded on day 8. At day 37, patients of Group B reported a net improvement of their MPS Symptoms: only five had experienced one episode of mild intensity [10–43 mm] and only one patient took paracetamol on one occasion [mean in all; number, 0.15 ± 0.06; intensity, mm 3.62 ± 1.72]. The average FS intensity [mm 57 ± 1.16] had also significantly improved with respect to values preceding the start of active TrP treatment on day 8 (p < 0.0001). 3.2. Fibromyalgia + joint pain 3.2.1. Main study period 3.2.1.1. Joint symptoms. Before the start of therapy, joint parameters did not differ significantly in Groups A and B. During the week of therapy in Group A but not Group B, both number and intensity of joint pain episodes significantly decreased with respect to the preceding week. On day 1, periarticular PPTs were significantly lower than normal in both groups, testifying the typical somatic hyperalgesia around a painful joint (p < 0.001) (Galletti et al., 1990). From day 1 to day 8, in Group A but not Group B, PPTs significantly increased (p < 0.0001), though remaining still significantly lower than normal (p < 0.001) (Table 2). During the week of treatment, paracetamol consumption was 1.5 ± 0.17 (SEM) in Group A and 3.46 ± 0.30 in Group B, the difference between the two groups was highly significant (p < 0.0001). 3.2.1.2. FS symptoms. Before the start of therapy, FS symptoms did not differ significantly in the two groups. During treatment, In

Group A but not Group B there was a significant reduction of the intensity of FS pain and number of positive TePs as well as an increase in TeP score (p < 0.0001) (Fig. 3). 3.2.1.3. Pain sensitivity in the non-painful area. In both groups, all thresholds were significantly lower than normal at day 1 (hyperalgesia) (p < 0.001). During the main phase of the study, in Group A but not Group B there was a significant increase in all thresholds (p < 0.0001) (Fig. 4), though all values always remained significantly lower than normal (p < 0.001). At day 8, only three patients of Group A requested further Hydrofor therapy vs all of the patients of Group B. The difference in request between the two groups was highly significant (p < 0.0001). Two Hydrofor applications were thus delivered on day 8 and day 11 in the three patients of Group A and all 28 patients of Group B. 3.2.2. Follow-up At day 30, only 5 of the 25 patients of Group A that had not been subjected to further therapy reported painful episodes in the days 8–30 period: three patients had one episode and two patients two episodes [mean in all: 0.28 ± 0.12 (SEM)]; their intensity was mildmoderate [20–42 mm of VAS; mean in all 5.79 ± 2.48] and required paracetamol assumption on three occasions. The average FS pain intensity over the same period in all 25 patients was mm 59.16 ± 2.09 (SEM), not significantly different from values of day 8. At day 37, joint symptoms had improved in all patients, with the three patients of Group A (subjected to two cycles of therapy) no longer experiencing acute joint episodes, and only 6 of the 28 patients of Group B presenting one crisis each (mean in the whole group: 0.18 ± 0.06) of intensity 10–43 mm (mean in all: mm

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Fig. 2. FS pain sensitivity in a non-painful area. Electrical pain thresholds in skin, subcutis and muscle and pressure pain thresholds in muscles of FS patients undergoing either active treatment of Myofascial Trigger Points (TrPs) (Group A, n = 34) or placebo-like treatment of TrPs (Group B, n = 34) (mean ± SEM). Legend as for Fig. 1. Comparison between day 4 and day 8 in Group A: p < 0.001 for all thresholds except in skin.

4.06 ± 1.74), requiring paracetamol only in two cases. FS symptoms were further reduced in the three patients of Group A (VAS: from mm 63, 56, 57 on day 8 to 52, 46, 50 on day 37) and were significantly reduced in the 28 patients of Group B [at day 37: mm 61.64 ± 1.42] with respect to day 8 (p < 0.0001). 3.3. Comparison of FS symptoms between A patients of protocol (1) and (2) At the end of the main phase of the study (day 8), and of the follow-up (day 30) the reduction of FS symptoms with respect to day 1 was slightly more pronounced for A patients of protocol (1) than for A patients of protocol (2), however the difference was not significant. 3.4. Normal subjects In the non-painful area, electrical thresholds were: mA 1.92 ± 0.08 in skin, 2.02 ± 0.14 in subcutis and 4.28 ± 0.11 in muscle. PPTs were: kgf 4.65 ± 0.07 [mean ± SEM]. PPTs in areas corresponding to TrPs of patients in protocol (1) were: kgf 4.04 ± 0.05 and PPTs in areas corresponding to painful joints of patients in protocol (2) were kgf 4.08 ± 0.06. 4. Discussion and conclusions The results of the study show that in fibromyalgia patients with concurrent myofascial pain syndromes due to trigger points or focal joint pain from osteoarthritis or microtraumas, local treatment

of the peripheral muscle/joint sources not only relieves local symptoms but also significantly improves the widespread FS symptoms in terms of reduction of both spontaneous diffuse pain and tenderness at all tender point sites. The results also show that this local treatment is able to induce a general desensitization of tissues, as there is an increase in pain thresholds to more than one stimulus modality (mechanical and electrical stimuli) in somatic structures of non-painful areas in FS patients undergoing active treatment but not placebo treatment. This increase is not likely to be attributed to a systemic effect of the drugs delivered locally to trigger points or painful joints for several reasons. TrP anaesthetic infiltration has been shown in a previous study in nonfibromyalgic patients to not produce any significant change in pain thresholds in a non-painful area (Affaitati et al., 2009). As regards Hydrofor, data from the literature show that systemic absorption of drugs delivered through this route is insignificant (Brizzi et al., 2004), and also preliminary results by our group in patients with joint pain without fibromyalgia show no significant change in pain thresholds in a neutral non-painful area (unpublished data). Furthermore, in both the TrP and joint examples the effects of desensitization in the present study are too longlasting (30 days) to be attributable to any possible direct effect of the drugs delivered in local therapy on the tissues of the distant, non-painful area. The decreased level of generalized hyperalgesia, as well as of spontaneous diffuse pain in the FS patients of our casuistry are thus likely to reflect other mechanisms, related to the hypothesized pathophysiology of FS. Mounting evidence indicates that patients with fibromyalgia experience abnormal pain amplification in the central nervous system (CNS) due to enhanced excitability of the spinal cord neurons

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Fig. 3. FS symptoms. FS patients undergoing either active treatment (Group A, n = 28) or placebo treatment (Group B, n = 28) of joint pain. Legend as for Fig. 1.

Fig. 4. FS pain sensitivity in a non-painful area. FS patients undergoing either active treatment (Group A, n = 28) or placebo treatment (Group B, n = 28) of joint pain. Legend as for Fig. 2.

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Table 2 Joint symptoms over 7 days before and 7 days after start of local joint therapy in 28 patients undergoing Hydrofor application (Group A) and 28 patients undergoing Placebo Hydrofor application. Mean ± SEM.

***

Type of treatment

Number of joint pain episodes before

Number of joint pain episodes after

Intensity of joint pain (mm of VAS) before

Intensity of joint pain (mm of VAS) after

PPTs at joint site (kgf) before

PPTs at joint site (kgf) after

Active joint treatment (Group A) Placebo joint treatment (Group B)

6.53 ± 0.30 7.00 ± 0.26

1.89 ± 0.23*** 6.61 ± 0.31 NS

59.78 ± 2.97 58.93 ± 2.64

35.11 ± 1.69*** 57.36 ± 2.97 NS

1.06 ± 0.06 1.13 ± 0.07

1.40 ± 0.05*** 1.21 ± 0.06 NS

p < 0.001, NS = not significant; comparison between before and after values.

that transmit nociceptive information to the brain (central sensitization). Spinal sensitization to pain in FS would also seem related to abnormalities in descending efferent pathways, i.e., dysfunction/impairment of the many neural systems that contribute to the descending inhibitory pathways (Abeles et al., 2007; Schweinhardt et al., 2008; Williams and Claw, 2009; Sommer, 2010). In this context, the suppression/reduction of the nociceptive input towards the CNS from powerful peripheral pain sources – such as trigger points or diseased joints – could impact on the diffuse FS symptoms by decreasing the level of central sensitization/amplification of pain signals in the patients. This effect would also seem dependent on the amount of peripheral nociceptive input from the local pain sources as the improvement in FS symptoms, especially the spontaneous diffuse pain, appeared slightly more marked in patients with FS + MPS, in whom trigger point treatment produced more effective results on MPS pain, than in patients with FS + joint disease in whom joint treatment was less effective on local articular pain. In fact, after 1-week treatment, FS pain intensity decreased by 30% in FS + MPS (where MPS number and intensity of episodes were reduced by 82% and 69%, respectively) vs a decrease of 22% in FS + joint disease (where joint number and intensity of pain episodes were reduced by 71% and 41%, respectively). Further research on the effects of different modalities and extents of peripheral pain treatments on FS symptoms will be needed to confirm this specific issue. In this study, FS was diagnosed based on the ACR criteria, where tender point count is an essential requisite. These criteria are at present being challenged by many and will probably be subject to substantial revision in the near future, with diagnosis involving assessment of fewer TePs than the actual 18, or even excluding TeP count and considering only symptom clusters (Bennett, 2009; Goldenberg, 2009; Wilke, 2009; Tastekin et al., 2010; Wolfe et al., 2010). In this perspective, it will thus be important to verify in future studies if also other typical FS symptoms, such as sleep disturbance, fatigue, physical impairment or affective dysfunction, actually benefit from treatment of peripheral nociceptive sources and/or if this treatment has differential effects in subgroups of patients with different clusters of symptoms/co-morbidities. However, preliminary studies show that the newly proposed symptom-based criteria, excluding tender point count, are less restrictive than the ones still valid at present. Patients so far identified as fibromyalgic according to ACR (1990) – as in the present study – would thus remain with this diagnosis with the new criteria (Cöster et al., 2008; Wolfe et al., 2010), suggesting that FS can be diagnosed for clinical purposes by both symptom-based and ACR criteria (strong consensus according to the Oxford Center for Evidence-Based Medicine) (Eich et al., 2008). At most, FS patients in this study are likely to be classified in the future as the extreme subgroup of the wider population of chronic widespread pain patients (Staud, 2009). Irrespective of this controversy, however, and while awaiting validation of the newly suggested guidelines for FS diagnosis, we believe that the results of the present study on one hand confirm the role of peripheral/local nociceptive sources as pain generators in the widespread pain symptoms of FS (Ge et al., 2009a,b; Staud

et al., 2009) and, on the other, show for the first time the clinical impact of treatment of these generators on the typical fibromyalgia pain complaints – widespread spontaneous musculoskeletal pain and tenderness. The extent of symptom decrease is not such to allow suspension of specific FS treatments, at least in patients with a high basal level of diffuse pain (close to 80 mm of VAS) as in the present casuistry. It is, however, marked enough – 22–30% – to allow either a possible dose reduction of chronically administered drugs for FS (with consequent reduction of side effects) or a better symptom control at the same doses, with obvious advantages for the patients. This is particularly important for a syndrome like fibromyalgia where management options available so far are still of limited effectiveness in a large percentage of cases (Carville et al., 2008; Arnold, 2009). Identification and treatment of peripheral pain generators are thus proposed as first approach to FS, before any other therapy is initiated, to optimize the global management of the patient’s suffering. Acknowledgements The study was supported by ‘‘G. D’Annunzio” University funds for research to Maria Adele Giamberardino. References Abeles AM, Pillinger MH, Solitar BM, Abeles M. Narrative review: the pathophysiology of fibromyalgia. Ann Int Med 2007;146:726–34. Affaitati G, Bellomo RG, Fabrizio A, Savini A, Lerza R. Effetti dell’idroelettroforesi nella patologia dolorosa articolare. In: Atti del Congresso Nazionale Ass. Naz. Spec. in Medicina dello Sport della Università ‘‘G. D’Annunzio”, Attività fisicosportiva nell’adulto e nell’anziano, Vittorio Veneto, 18–21 Giugno; 2006. p. 630–8. Affaitati G, Fabrizio A, Costantini R, Giamberardino MA. Treatment of peripheral pain generators in fibromyalgia. Abstracts of the 13th World Congress on Pain (ISBN 978-0-931092-87-9), Omnipress, PM093; 2010. Affaitati G, Fabrizio A, Savini A, Lerza R, Tafuri E, Costantini R, et al. A randomized, controlled study comparing a lidocaine patch, a placebo patch, and anesthetic injection for treatment of trigger points in patients with myofascial pain syndrome: evaluation of pain and somatic pain thresholds. Clin Ther 2009;31:705–20. Ardic F, Kahraman Y, Kacar M, Kahraman MC, Findikoglu G, Yorgancioglu ZR. Shoulder impingement syndrome: relationships between clinical, functional, and radiologic findings. Am J Phys Med Rehabil 2006;85:53–60. Arnold LM. Advances in the management of fibromyalgia. CNS Spectrums 2009;14(8):12–6 (discussion 17–18). Bennett R. Fibromyalgia: present to future. Curr Rheumatol Rep 2005;7:371–6. Bennett RM. Clinical manifestations and diagnosis of fibromyalgia. Rheum Dis Clin North Am 2009;35:215–32. Bradley LA. Pathophysiology of fibromyalgia. Am J Med 2009;122(12):22–30. Brizzi A, Giusti A, Giacchetti P, Stefanelli S, Provinciali L, Ceravolo MG. A randomised controlled trial on the efficacy of hydroelectrophoresis in acute recurrences in chronic low back pain patients. Eura Medicophys 2004;40:303–9. Buskila D, Sarzi-Puttini P, Ablin JN. The genetics of fibromyalgia syndrome. Pharmacogenomics 2007;8:67–74. Cakit BD, Taskin S, Nacir B, Unlu I, Genc H, Erdem HR. Comorbidity of fibromyalgia and cervical myofascial pain syndrome. Clin Rheumatol 2010 [Epub ahead of print]. Carli G, Suman AL, Biasi G, Marolongo R. Reactivity to superficial and deep stimuli in patients with chronic musculoskeletal pain. Pain 2002;100:259–69. Carville SF, Arendt-Nielsen S, Bliddal H, Blotman F, Branco JC, Buskila D, et al. EULAR evidence based recommendations for the management of fibromyalgia syndrome. Ann Rheum Dis 2008;67(4):536–41. Clauw DJ. Fibromyalgia: an overview. Am J Med 2009;122(12):3–13.

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