Regenerative injection therapy and repetitive transcranial magnetic stimulation in primary fibromyalgia treatment: A comparative study

Abstract

OBJECTIVE:

This study compared the effectiveness of regenerative injection therapy (RIT), i.e. prolotherapy, and repetitive transcranial magnetic stimulation (rTMS) in the treatment of fibromyalgia syndrome.

PATIENTS AND METHODS:

This study included 120 female, age-matched fibromyalgia patients. All patients underwent a clinical examination, pain assessment by VAS, assessment of tender points, psychiatric and functional assessment using the Beck Depression Inventory (BDI), Fibromyalgia Impact Questionnaire Revised (RFIQ), and measurement of cortical auditory evoked potentials CAEPs elicited at 1000 Hz. Patients were divided into two equal groups; Group 1 received prolotherapy three times, two weeks apart, and Group 2 received rTMS sessions every other day for one month. Assessment was performed before treatment, immediately after treatment, and one month later.

RESULTS:

A significant improvement of pain measured by the mean score of VAS was remarked in Group 1 compared to Group 2 immediately after treatment and one month later. There was statistically significant difference of mean scores for the number of tender points in Group 1 compared to Group 2 after treatment and one month later. The patients improved functionally, with a statistically significant difference in mean score of RFIQ, in Group 1 compared to Group 2 one month after treatment. However, there was a significant difference in mean score of BDI in Group 2 compared to Group 1 after treatment and one month later. Further, CAEPs showed better improvement, with a significant difference in Group 2, one month after treatment.

CONCLUSION:

RIT had the advantage in clinical and functional improvement in fibromyalgia patients, while rTMS had better results regarding depression and the cortical component of AEPs. These results might draw attention to the evaluability of a combination of both techniques for a better therapeutic response.

Keywords

Regenerative injection therapy repetitive transcranial magnetic stimulation fibromyalgia syndrome

1. Introduction

Fibromyalgia syndrome (FMS) is a chronic, potentially disabling condition defined by core symptoms of widespread pain, stiffness, fatigue, sleep disturbance, and cognitive dysfunction [1]. It is now considered one phenotype of a much broader spectrum of disorders, described as central sensitivity syndrome (CSS), that overlap substantially in individual patients [2]. Recently, development of FMS has been linked to some genes and various infectious agents; it predominates mainly in women, impacting two to four percent of the population [3].

One of the non-pharmacological treatments of FMS is regenerative injection therapy (RIT) or prolotherapy. It involves injecting small amount of solution (dextrose, phenol, glycerin and, most recently, platelet rich plasma and stem cell) into multiple painful ligament and tendon insertions (enthesis), common trigger points, as well as into the adjacent joint spaces to induce healing of the injured structures. It is presumed to act by stimulating weakened structures such as ligaments and tendons to strengthen, tighten and heal through the proliferation of cells [4].

Brain repetitive transcranial magnetic stimulation (rTMS) is another therapeutic modality for fibromyalgia. It modifies cortical and deep brain areas, through an electromagnetic field generated over the scalp, by decreasing or increasing cortical excitability (when using low- or high-frequency protocols). Its effect is exerted by modulating pain pathways such as the descending (inhibitory) pathways and modulating social-affective regions of the brain such as the right temporal lobe [5].

This study compared the efficacy of RIT (prolotherapy) and rTMS in the treatment of patients with primary fibromyalgia.

2. Patients and methods

This study was conducted with 120 patients selected from the out-patients clinic of the Physical Medicine, Rheumatology and Rehabilitation Department and the Neurology Department, Tanta University Hospitals. Patients met ACR 2010 preliminary diagnostic criteria for fibromyalgia syndrome.

Excluded were patients with secondary fibromyalgia, patients with systemic disease or chronic arthritis such as RA, SLE, pregnant and nursing women, patients with bleeding tendency or using anticoagulant, patients with active infection or cancer, complete rupture of a tendon or alignment, patients with muscle diseases, diabetes mellitus, thyroid dysfunction, patients with seizures or abnormal brain electrical activity, primary psychiatric or neurological disorders, patients with pacemakers, recent head trauma, auditory problems or drug abuse. We explainthe proceduresto patients and all patients gave their informed consent prior to their inclusion and the study was approved by the ethical committee of Tanta University Hospital in accordance with the declaration of Helsinki.

2.1 Group 1

Sixty patients with FMS received prolotherapy: three injections, two weeks apart.

2.2 Procedure

The injected solution consisted of 25% dextrose to make a 12.5% soft tissue solution (1/2 volume of 10 ml syringe), xylocaine 0.3% (1 ml of 3% xylocaine over 10 ml solution); bacteriostatic water was recommended as a diluent. 0.5–1 ml of solution was injected in each trigger point as well as tender ligaments and tendinous insertion points. The prolotherapist used his fingertip to palpate potential pain referral sources for the patient’s clinical complaints. Injection sites were cervical inter-transverse ligaments, posterior-superior trapezius, infraspinatus, common extensors, iliolumbar, and sacroiliac ligament [6, 7].

2.3 Group 2

Sixty patients with FMS received 15 sessions of high frequency, 10 Hz r, TMS every other day for one month. The electrodes were applied to the left dorsolateral prefrontal cortex (DLPFC).

2.4 Procedure

The TMS machine used was the Magstim 200 repetitive pulse stimulator by Magstim Company, Whitland Wales, UK. The cortical target was DLPFC, a functional, rather than anatomical, structure. This region lies in the middle frontal gyrus (i.e., lateral part of Brodmann’s area), 9 and 46, and it is considered the end point for the dorsal pathway that tells the brain how to interact with the stimuli [8]. The same stimulation frequency was used for all patients, parameters of antidepressant and anti-nociceptive effects were: 10 Hertz – pulse train duration (on time) five seconds, inter-train interval (off time) ten seconds (15 second cycle time). Additionally, stimulation-train duration and inter-stimulus intervals were determined such that they comply with current published rTMS safety guidelines [9].

2.5 Clinical assessment

Clinical assessment included the following:

1.
Complete medical history with complaint analysis.
2.
General and locomotor system examination, including 18 tender points.
3.
Assessment of pain by VAS, where 0 represents no pain, and 100 represents unbearable pain [10].
4.
Number of tender points. According to the ACR 1990 diagnostic criteria for fibromyalgia syndrome, there should be at least 11 of the 18 tender points [11].
5.
Assessment of disability and current health status using the FIQR, including three domains (function, overall impact, symptoms). The total maximal score of the FIQR is 100. Higher scores reflect a significant negative impact or severe symptoms [12].
6.
Assessment of depression using the BDI, with minimal range $=$ 0–13, mild depression $=$ 14–19, moderate depression $=$ 20–28, and severe depression $=$ 29–63 [13, 14].
7.
Measurement of CAEPs to assess patients’ cognitive function and hypervigilance [15]. The slow cortical response is composed of a positive wave (P1) of about 50 ms latency, a large negative wave (N1) at about 80 to 100 ms, and a subsequent positive wave (P2) at about 180 to 200 ms, followed by a negative wave (N2) at about 220 to 270 ms. CAEPs at a frequency of 1000-Hz, tone intensity was constant (60, 70, 80, and 90 dB in successive series) [16].

The assessment was performed before treatment, at the end of treatment, and one month after treatment.
2.6 Laboratory assessment

Laboratory assessment included complete blood count (CBC), erythrocyte sedimentation rate (ESR), serum CRP (C-reactive protein), and thyroid stimulating hormones (TSH).

2.7 Statistical analysis

Statistical analysis was performed using statistical software package SPSS, Version 10. Descriptive quantitative data were expressed as ranges, mean, and SD and as numbers and percentages for qualitative data. Student’s t-test was used to compare between two independent means, and one-way analysis of variance (ANOVA) was used for comparison between the two studied groups. A P-value less than 0.05 was considered significant and a P-value less than 0.01 was considered highly significant. All results were tabulated and statistically analyzed [17].

3. Results

The two studied groups were matched in age and sex, with no significant difference between them in terms of disease duration. There was a significant decrease of mean score of VAS and number of tender points after treatment and one month later compared to before treatment in both groups, with a statistically significant difference in Group 1 compared to Group 2 one month after treatment, but not immediately after treatment according to VAS. There was a statistically significant difference in mean number of tender points in Group 1 compared to Group 2 after treatment and one month later (Table 1).

Table 1
Comparison of mean scores of VAS and mean the number of tender points between the studied two groups of fibromyalgia before, after treatment, and at follow up

VAS	Group 1	Group 2	P
	(regenerative	(rTMS)
	injection therapy)	( $n=$ 60)
	( $n=$ 60)
Before treatment
Range	70–90	50–90	0.002 ${}^{*}$
Mean $\pm$ SD	82.67 $\pm$ 6.19	71.43 $\pm$ 10.69
After treatment
Range	40–70	30–70	0.112
Mean $\pm$ SD	57.47 $\pm$ 9.57	51.43 $\pm$ 10.69
Follow up
Range	10–40	30–50	$<$ 0.001 ${}^{*}$
Mean $\pm$ SD	33.71 $\pm$ 11.32	47.14 $\pm$ 7.56
Number of tender points
Before treatment
Range	11–17	12–17	0.554
Mean $\pm$ SD	13.25 $\pm$ 1.83	13.71 $\pm$ 2.29
After treatment
Range	5–14	9–15	0.027 ${}^{*}$
Mean $\pm$ SD	9.20 $\pm$ 2.69	11.43 $\pm$ 2.57
Follow up
Range	4–12	8–14	$<$ 0.001 ${}^{*}$
Mean $\pm$ SD	6.00 $\pm$ 2.44	10.86 $\pm$ 2.85

VAS: visual analogue scale, rTMS: Repetitive transcranial magnetic stimulation, values are significant at $p<$ 0.05.

Table 2

Comparison of mean values of revised fibromyalgia impaction questionnaire scores between the studied two groups with fibromyalgia before, after treatment, and at follow up

Revised fibromyalgia	Group 1	Group 2	P
impaction questionnaire
scores (FIQR)
Before treatment
Range	45–73	46–80	0.369
Mean $\pm$ SD	61.95 $\pm$ 9.75	65.0 $\pm$ 8.64
After treatment
Range	33–67	36–70	0.294
Mean $\pm$ SD	48.42 $\pm$ 8.87	52.43 $\pm$ 11.27
Follow up
Range	19–43	31–65	$<$ 0.001 ${}^{*}$
Mean $\pm$ SD	31.23 $\pm$ 10.67	51.71 $\pm$ 12.57

Values are significant at $p<$ 0.05.

Table 3

Comparison of mean scores of Beck Depression Inventory (BDI) scale between the studied two groups with fibromyalgia before, after treatment, and at follow up

Beck Depression	Group 1	Group 2	P
Inventory scale
Before treatment
Range	19–41	17–39	0.469
Mean $\pm$ SD	26.68 $\pm$ 4.56	25.57 $\pm$ 3.69
After treatment
Range	17–32	8–28	$<$ 0.001 ${}^{*}$
Mean $\pm$ SD	22.75 $\pm$ 3.95	15.14 $\pm$ 4.58
Follow up
Range	11–23	4–22	0.0002 ${}^{*}$
Mean $\pm$ SD	16.44 $\pm$ 3.49	10.14 $\pm$ 4.63

Values are significant at $p<$ 0.05.

Table 4

Comparison of CAEPs recorded from two studied groups of fibromyalgia elicited by 1000 Hz at follow up

CAEPs 1000 Hz	Group 1		Group 2		P
80 Db
P1
Mean $\pm$ SD	61.56	$\pm$ 13.35	34.86	$\pm$ 5.27	$<$ 0.001 ${}^{*}$
N1
Mean $\pm$ SD	115.87	$\pm$ 17.67	79.67	$\pm$ 7.70	$<$ 0.001 ${}^{*}$
P2
Mean $\pm$ SD	186.54	$\pm$ 21.39	155.34	$\pm$ 18.79	0.001 ${}^{*}$
N2
Mean $\pm$ SD	268.75	$\pm$ 32.96	252.98	$\pm$ 13.83	$<$ 0.001 ${}^{*}$
90 Db
P1
Mean $\pm$ SD	55.78	$\pm$ 14.87	37.84	$\pm$ 11.75	$<$ 0.001 ${}^{*}$
N1
Mean $\pm$ SD	117.00	$\pm$ 17.84	85.83	$\pm$ 25.98	$<$ 0.001 ${}^{*}$
P2
Mean $\pm$ SD	178.80	$\pm$ 24.40	157.54	$\pm$ 19.74	$<$ 0.001 ${}^{*}$
N2
Mean $\pm$ SD	272.61	$\pm$ 25.84	225.12	$\pm$ 23.56	0.001 ${}^{*}$

CAEPs: Cortical auditory evoked potentials, values are significant at $p<$ 0.05.

There was a significant decrease of the mean score of FIQR after treatment and one month later compared with before treatment in the two studied groups with statistically significant difference in Group 1 compared to Group 2 one month after treatment. However, there was no significant difference immediately after treatment between the two groups (Table 2). There was a significant decrease of the mean score of BDI after treatment and one month later compared to before treatment in the two groups, with statistically significant difference in Group 2 compared to Group 1 (Table 3).

With CAEPs as a tool for follow up of patients with fibromyalgia after treatment, our study showed a significant difference in Group 2 compared to Group 1 regarding CAEP latencies elicited by 1000 Hz at 80 and 90 dB intensities one month after treatment (Table 4).

4. Discussion

FMS is a poly-symptomatic syndrome of chronic widespread pain often accompanied by fatigue, non-restorative sleep, and visceral hyperalgesia. It is a common cause of chronic widespread pain with multiple tender points that are widely and symmetrically distributed throughout the body and lasting longer than three months [18]. While the mechanism of chronic pain in FMS remains unclear, cumulative evidence suggests that amplification of central pain plays a key role in the fundamental pathogenesis of FMS. It refers to augmented pain and sensory processing within the spinal cord and brain sometimes termed “central sensitization” [19].

Based on epidemiological and clinical grounds, the development of FMS has recently been linked with various infectious agents such as Hepatitis C and B. The increased risk of developing FMS in families, together with other diseases which are common co-morbidities to FMS, suggests a possible link with certain genes. Three are already identified and found to be present in 35 percent of the FMS cohort and are associated with higher levels of inflammatory cytokines and determine individual sensitivity and reaction to pain, quality of the anti-nociceptive system and complex biochemistry of pain sensation [3, 20].

RIT, or prolotherapy, was developed by pain management practitioners. The groundwork for this growing field was created through Hackett’s original works. An amalgam of injection techniques is currently being used in the United States [21].

Prolotherapy involves injection at the enthesis (attachment site) of a damaged ligament or tendon with material that directly or indirectly stimulates inflammation of the body, or a substance that acts directly or indirectly as a growth factor for ligament repair with new healthy collagen tissue in the strength fibers of these structures [22].

George S. Hackett, MD, who coined the term in the mid-1950s, described prolotherapy as follows:

The treatment consists of the injection of a solution within the relaxed ligament and tendon which will stimulate the production of new fibrous tissue and bone cells via the stimulation of growth factors via the inflammatory healing cascade, as well as reduction of neurogenic inflammation, that will strengthen the ‘weld’ of fibrous tissue and bone to stabilize the articulation and permanently eliminate the disability [4].

Dextrose is the perfect substance touse in prolotherapy because it is water-soluble and a natural component of blood chemistry which can be safely injected into multiple areas and in large quantities. Direct, anosmotic, and inflammatory growth effect are different mechanisms for which the prolotherapy is supposed to work. Dextrose injections below a 10 percent solution directly stimulate proliferation of cells and tissue without causing a histological inflammatory reaction. When dextrose is injected in greater than a 10 percent solution, it is presumed to cause an osmotic (concentrated) gradient outside of the cells where it is injected. This causes some cells to lose water and lyse, with the net effect being an influx of growth factors and inflammatory cells that initiates the wound-healing cascade to that specific area. The assumed net result is the deposition of new collagen into injured structures, such as ligaments and tendons. When exposed to an extracellular dextrose concentration of only 0.5 percent, normal human cells begin to multiply and produce a number of growth factors, including platelet-derived growth factor, transforming growth factor-beta (TGF- $\beta$ ), epidermal growth factor, basic fibroblast growth factor, insulin-like growth factor, and connective tissue growth factor. These growth factors are related to the repair, health, and growth of tendons, ligaments and other soft tissue [4].

Kim et al. [23] reported on the treatment of 67 patients with chronic musculoskeletal pain with two monthly sessions of 15 percent dextrose prolotherapy. VAS showed a statistically significant reduction in pain from 7.0 to 4.31 after the first set of injections, which fell to 2.55 after the second series of injections.

Cusi et al. [24] assessed 25 subjects with sacroiliac joint dysfunction and pain with a documented failure of load transfer (disability), refractory to six months or more of physical therapy. They used a strong prolotherapy solution of 18 percent dextrose, delivered in three sets of injections over 12 weeks. Compared with the baseline, pain and disability scores on three multidimensional outcome measures significantly improved at 26 month follow-up.

Khan et al. [25] evaluated 37 subjects with refractory coccygodynia using 25 percent dextrose in three injection sessions over two months. Evaluation of average pain scores using VAS resulted in a significant reduction from the baseline score of 8.5 to 2.5 points at two months. The authors reported “good” pain relief for 30 of 37 subjects.

The discussion by Miller et al. regarding the efficacy of prolotherapy for axial pain and disability by [26] was valuable. They assessed prolotherapy for leg pain due to moderate to-severe degenerative disc disease as determined by computed tomography (CT) discography. Seventy-six subjects who failed physical therapy and had substantial but temporary pain relief with two fluoroscopically-guided epidural steroid injections were included. After an average of 3.5 biweekly sessions of fluoroscopically-guided injections to the relevant disc space with 25 percent dextrose with bupivacaine, 43 percent of participants showed a significant, sustained treatment response of 71 percent improvement in pain score, with VAS score at 8.9 ( $\pm$ 1.4), 2.5 ( $\pm$ 2.0), and 2.6 ( $\pm$ 2.2) at baseline, two months, and 18 months, respectively.

Maxwell et al. [27] conducted a series of well-designed cases to assess whether prolotherapy, administered during a mean of four injection sessions, at six-week intervals, would decrease pain in 36 adults with painful Achilles tendinopathy. In this study, 25 percent dextrose solution was injected into hypoechoic regions of the Achilles tendon under ultrasound guidance.

Also, Reeves [28] treated 31 consecutive severe fibromyalgia patients with 12.5% dextrose prolotherapy, an average of 3.5 times. Patients reported a 32.1 percent reduction in pain levels in more than 16 areas of the body.

Noninvasive induction of intracerebral currents over several sessions of stimulation is the principle of rTMS, a brain intervention that modulates activity in discrete cortical regions and associated neural circuits. Regular, high-frequency (5–30 Hz) stimulation increases cortical excitability (long-term potentiation-like effect), whereas low-frequency (0.3–1 Hz) stimulation decreases cortical excitability (long term depression-like effect) [29, 30].

High-frequency rTMS over motor cortex increases motor evoked potentials (MEP), a measure of cortical excitability, and low frequency TMS decreases MEP. Regarding mood, it is hypothesized that chronic repetitive stimulation of the prefrontal cortex initiates a cascade of events in the prefrontal cortex and connected limbic regions [31]. Prefrontal TMS sends information to critical mood-regulating regions including the cingulate gyrus, orbitofrontal cortex, insula, and hippocampus, and may induce dopamine release in the caudate nucleus [31, 32, 33].

Repetitive transcranial magnetic stimulation (rTMS) may reduce fibromyalgia pain by enhancing intracortical modulation. Regardless of mechanisms, optimal TMS parameters and locations for fibromyalgia are not clear. Sampson et al. [34] used low-frequency rTMS over the right dorsal lateral prefrontal cortex (RDLPFC). This produced a reduction in pain in four patients with fibromyalgia. This was a secondary analysis from a larger study, limiting conclusions. In a replication study by Carretero et al. [35] the results were negative; however, subjects were given 400 fewer pulses per session and thus may have received sub-therapeutic doses. Passard et al. [36] studied high-frequency rTMS in motor cortex and found a reduction in fibromyalgia pain that remained significant for two weeks.

Patients with fibromyalgia have abnormalities in central pain modulation and may have abnormalities in endogenous opioid systems [37] and enhanced spontaneous pain related to enhanced insula connectivity with default mode network circuitry [38]. Fibromyalgia subjects can have higher resting motor thresholds, motor evoked potentials, lower intracortical facilitation, and short intracortical inhibition, which suggest abnormal intracortical modulation involving GABAergic and glutamatergic mechanisms [39]. Fibromyalgia subjects have been shown to have less rostral anterior cingulate cortex (ACC) activity with pain provocation, suggesting decreased activity of pain inhibition circuitry. rTMS to DLPFC may reduce fibromyalgia pain via modulation of pain processing circuitry [40].

Pain modulation circuitry may involve the prefrontal cortex (PFC), ACC, periaqueductal gray and ventral medial medulla [41]. The PFC may be directly involved in placebo analgesia via the release of endogenous opioids in these subcortical regions and reducing pain transmission [42]. Placebo analgesia can be experimentally blunted with opiate antagonists [43]. Furthermore, the placebo response can be transiently blocked with low-frequency TMS to bilateral DLPFC in healthy volunteers [44].

In our view, the functional improvement induced by rTMS may be due to modulation of neuronal circuits, not only not only because of its analgesic effect. Also, improving the depressed mood in our patients may partly be a reflection of pain reduction. Other trials have also seen reductions in TMS procedural pain and overall pain levels before antidepressant effects when stimulating at 10 Hz, LDLPFC rTMS [45, 46].

A Cochrane Review that analyzed TMS antidepressant trials until 2001 concluded that there is no strong evidence of the effectiveness of TMS to treat depression. Small sample size, lower stimulation intensities, and shorter treatment courses were the primary methodological deficiencies in those trials [47], however the FDA approved high-frequency rTMS for the treatment of unipolar, nonpsychotic, depression after failing to respond to one antidepressant [10, 48].

5. Conclusion

Improved clinical symptoms were achieved, with better functional performance, in fibromyalgia patients on RIT, while psychiatric symptoms and cortical auditory response were improved through the central effect of rTMS.

The additional effects of RIT and rTMS as two treatment modalities may be of great value in the treatment of patients with primary fibromyalgia.

Footnotes

Conflict of interest

None to report.

References

Wolfe

Clauw

Fitzcharles

Goldenberg

Katz

Mease

, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken) 2010; 62: 600-10.

Smith

Harris

Clauw

. Fibromyalgia: an afferent processing disorder leading to a complex pain generalized syndrome. Pain Physician 2011; 14: 217-45.

Binkiewicz-Glińska

Bakuła

Tomczak

Landowski

Ruckemann-Dziurdzińska

Zaborowska-Sapeta

, et al. Fibromyalgia Syndrome – a multidisciplinary approach. Psychiatr Pol 2015; 49: 801-10.

Hauser

Baird

. Evidence-Based Use of Dextrose Prolotherapy for Musculoskeletal Pain: A Scientific Literature Review. J of Prolotherapy 2011; 3: 765-89.

Boyer

Dousset

Roussel

. rTMS in fibromyalgia: a randomized trial evaluating QoL and its brain metabolic substrate. Neurology 2014; 82: 1231-1238.

Shallenberger

HMD

. Prolozone-Regenerating Joints and Eliminating Pain. Journal of Prolotherapy 2011; 3: 630-38.

Rabago

Slattengren

Zgierska

. Prolotherapy in Primary Care Practice. Prim Care 2010 Mar; 37(1): 65-80.

Ahdab

Ayache

Brugieres

Goujon

Lefaucheur

. Comparison of “standard” and “navigated” procedures of TMS coil positioning over the motor, premotor and prefrontal targets in patients with chronic pain and depression. Neurophysiol Clin 2010; 40(1): 27-36.

Rossi

Hallett

Rossini

Pascual-Leone

. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology 2009; 120(12): 2008-2039.

10.

Lee

Hobden

Stiell

Wells

. Clinically important change in the visual analog scale after adequate pain control. Academic Emergency Medicine 2003; 10: 1128-30.

11.

Harth

Nielson

. The fibromyalgia tender points: use them or lose them? A brief review of the controversy. Rheumatol 2007; 34: 914-22.

12.

Bennett

Friend

Jones

Ward

Han

Ross

. The Revised fibromyalgia Impaction questionnaire Validation and Psychometric properties. Arthritis Research Therapy 2009; 11: R120.

13.

Kühner

Bürger

Keller

Hautzinger

. Reliability and validity of the Revised Beck Depression Inventory (BDI-II). Results from German samples. Nervenarzt 2007 Jun; 78(6): 651-6.

14.

Smarr

Keefer

. Measures of depression and depressive symptoms: Beck Depression Inventory-II (BDI-II), Center for Epidemiologic Studies Depression Scale (CES-D), Geriatric Depression Scale (GDS), Hospital Anxiety and Depression Scale (HADS), and Patient Health Questionnaire-9 (PHQ-9). Arthritis Care & Research 2011; 63(Suppl 11): S454-66.

15.

González

Mercado

Barjola

Carretero

López-López

Bullones

, et al. Generalized hypervigilance in fibromyalgia patients: An experimental analysis with the emotional Stroop paradigm. J Psychosom Res 2010; 69: 279-287.

16.

Purdy

Katsch

Dillon

. Aided cortical auditory evoked potentials for hearing instrument evaluation in adults. Basel: Phonak AG 2005; 115-127.

17.

Dawson

Trapp

. Reading the medical literature: Basic & Clinical Biostatistics. Lange Medical Book/McGraw – Hill. Medical Publication Division, New York. 3

{}^{\text{rd}}

ed., 2001, Ch. 7–9, PP 161-218 and Ch. 13, PP 305-314.

18.

Hadianfard

Hosseinzadeh Parizi

. A randomized clinical trial of fibromyalgia treatment with acupuncture compared with fluoxetine. Iranian Red Crescent Medical Journal 2012; 14: 631-40.

19.

Baek

Seok

Koo

Kim

. Lengthened Cutaneous Silent Period in Fibromyalgia Suggesting Central Sensitization as a Pathogenesis. PLoS One 2016; 11: e0149248.

20.

Di Tella

Castelli

Colonna

Fusaro

Torta

Ardito

, et al. Theory of mind and emotional functioning in fibromyalgia syndrome: an investigation of the relationship between social cognition and executive function. M. PLoS One 2015; 10: e0116542.

21.

D’Agostino

. Regenerative Injection Therapy (Prolotherapy) for the treatment of Chronic Pain. Techniques in Orthopaedics 2003; 18: 8-16.

22.

Regenerative Injection Therapy (RIT): Effectiveness and Appropriate Usage by the Florida Academy of Pain Management June 30 th, 2001. Available at fapm.med.new.net and printed in The Pain Clinic, June 2002, volume 4, number 3. (Comprehensive review and referencing of available Prolotherapy literature – 138 articles).

23.

Kim

Shin

Seo

. The effect of Prolotherapy for the chronic pain of musculoskeletal system. The Journal of the Korean Academy of Rehabilitation Medicine 2001; 25(1): 128-33.

24.

Cusi

Saunders

Hungerford

Wisbey-Roth

Lucas

Wilson

. The use of prolotherapy in the sacroiliac joint. Br J Sports Med 2008; 44: 100-4.

25.

Khan

Kumar

Varshney

Trikha

Yadav

. Dextrose prolotherapy for recalcitrant coccygodynia. J Orthop Surg 2008; 16: 27-29.

26.

Miller

Mathews

Reeves

. Treatment of painful advanced internal lumbar disc derangement with intradiscal injection of hypertonic dextrose. Pain Physician 2006; 9: 115-21.

27.

Maxwell

Ryan

Taunton

Gillies

Wong

. Sonographically guided intratendinous injection of hyperosmolar dextrose to treat chronic tendinosis of the Achilles tendon: a pilot study. AJR Am J Roentgenol 2007; 189: 215-20.

28.

Reeves

. Treatment of consecutive severe fibromyalgia patients with Prolotherapy. Journal of Orthopedic Medicine 1994; 16: 84-8.

29.

Chen

Seitz

. Changing cortical excitability with low-frequency magnetic stimulation. Neurology 2001; 57(3): 379-380.

30.

Hallett

. Transcranial magnetic stimulation: a primer. Neuron 2007; 55(2): 187-199.

31.

Helfrich

Pierau

Freitag

Roeper

Ziemann

Bender

. Monitoring Cortical Excitability during Repetitive Transcranial Magnetic Stimulation in Children with ADHD: A Single-Blind, Sham-Controlled TMS-EEG Study. PLOS ONE www.plosone.org. 2012; 7(11): e50073.

32.

Paus

Castro-Alamancos

Petrides

. Cortico-cortical connectivity of the human mid-dorsolateral frontal cortex and its modulation by repetitive transcranial magnetic stimulation. Eur J Neurosci 2001; 14(8): 1405-1411.

33.

Strafella

Paus

Barrett

Dagher

. Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J Neurosci 2001; 21(15): RC157.

34.

Sampson

Rome

Rummans

. Slow-frequency rTMS reduces fibromyalgia pain. Pain Med 2006; 7(2): 115-118.

35.

Carretero

Martin

Juan

Pradana

Martin

Carral

, et al. Low-Frequency Transcranial Magnetic Stimulation in Patients with Fibromyalgia and Major Depression. Pain Med 2009; 4: 4.

36.

Passard

Attal

Benadhira

Brasseur

Saba

Sichere

, et al. Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia. Brain 2007; 130(Pt 10): 2661-2670.

37.

Baraniuk

Whalen

Cunningham

Clauw

. Cerebrospinal fluid levels of opioid peptides in fibromyalgia and chronic low back pain. BMC Musculoskelet Disord 2004; 5(48): 48.

38.

Napadow

LaCount

Park

As-Sanie

Clauw

Harris

. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum 2010; 62(8): 2545-2555.

39.

Mhalla

de Andrade

Baudic

Perrot

Bouhassira

. Alteration of cortical excitability in patients with fibromyalgia. Pain 2010; 149(3): 495-500.

40.

Jensen

Kosek

Petzke

Carville

Fransson

Marcus

, et al. Evidence of dysfunctional pain inhibition in Fibromyalgia reflected in rACC during provoked pain. Pain 2009; 144(1-2): 95-100.

41.

Petrovic

Kalso

Petersson

Ingvar

. Placebo and opioid analgesia-imaging a shared neuronal network. Science 2002; 295(5560): 1737-1740.

42.

Wager

Rilling

Smith

Sokolik

Casey

Davidson

, et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 2004; 303(5661): 1162-1167.

43.

Kedzior

Rajput

Price

Lee

Martin-Iverson

. Cognitive correlates of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression – a pilot study. BMC Psychiatry 2012; 12: 163.

44.

Krummenacher

Candia

Folkers

Schedlowski

Schonbachler

. Prefrontal cortex modulates placebo analgesia. Pain 2010; 148(3): 368-374.

45.

Anderson

Kavanagh

Borckardt

Nahas

Kose

Lisanby

, et al. Decreasing procedural pain over time of left prefrontal rTMS for depression: initial results from the open-label phase of a multi-site trial (OPT-TMS). Brain Stimul 2009; 2(2): 88-92.

46.

Avery

Holtzheimer

Fawaz

Russo

Neumaier

Dunner

, et al. Transcranial Magnetic Stimulation Reduces Pain in Patients With Major Depression: A Sham-Controlled Study. J Nerv Ment Dis 2007; 195(5): 378-381.

47.

Rodriguez-Martin JosÈ

Barbanoj JosÈ

Schlaepfer

Clos Susana

PÈrez

Kulisevsky

, et al. Cochrane Database of Systematic Reviews: Reviews 2001. John Wiley & Sons, Ltd; Chichester, UK: 2001. Transcranial magnetic stimulation for treating depression.

48.

Schutter

. Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. Psychol Med 2009; 39(1): 65-75.

Regenerative injection therapy and repetitive transcranial magnetic stimulation in primary fibromyalgia treatment: A comparative study

Abstract

OBJECTIVE:

PATIENTS AND METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Patients and methods

2.1 Group 1

2.2 Procedure

2.3 Group 2

2.4 Procedure

2.5 Clinical assessment

2.7 Statistical analysis

3. Results

Table 1 Comparison of mean scores of VAS and mean the number of tender points between the studied two groups of fibromyalgia before, after treatment, and at follow up

5. Conclusion

Footnotes

Conflict of interest

References

Table 1
Comparison of mean scores of VAS and mean the number of tender points between the studied two groups of fibromyalgia before, after treatment, and at follow up