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Ther Adv Musculoskelet Dis. 2010 April; 2(2): 105–118.
PMCID: PMC3034142
NIHMSID: NIHMS240806

Botulinum Toxin Therapy for Osteoarticular Pain: An Evidence-Based Review

Abstract

Botulinum (BoNT) toxin has been used for its muscle-paralyzing action in conditions such as treatment of wrinkles, cervical dystonia and blephrospasm. There is preclinical and emerging clinical evidence of another mechanism of action of BoNT, namely, an antinociceptive action. In this review, we provide an evidence-based review of clinical studies of BoNT in osteoarticular conditions, such as osteoarthritis, tennis elbow, low back pain, and hand pain. Many randomized controlled trials (RCTs) found evidence of short-term efficacy of an injection of BoNT in relief of pain, and in some cases, improvement of function and quality of life. However, more clinical trials are needed to better define the clinical use of BoNT for treatment of refractory osteoarticular pain.

Keywords: arthritis, Botulinum toxin, pain, therapy

Introduction

Recent population surveys have reported that 22–28% of adults in the US reported physician-diagnosed arthritis [Huijnen et al. 2006; Layeeque et al. 2004]. Arthritis and rheumatism are the leading causes of disability in adults aged 18 years and over in the US [Centers for Disease Control and Prevention, 2009]. In a European survey of prevalence of pain in the general population, moderate to severe pain lasting 6 months or longer was reported by 19% of respondents, of whom 40% (~8% of all respondents) had joint pain due to osteoarthritis and rheumatoid arthritis [Breivik et al. 2006], the two most common types of arthritic conditions in the population [Lawrence et al. 1998]. Both osteoarthritis and rheumatoid arthritis are associated with significant joint pain and functional limitations [Hunter et al. 2009; Bjork et al. 2007] and deficits in health-related quality of life [Slatkowsky-Christensen et al. 2007; Salaffi et al. 2005; Kvien and Uhlig, 2005]. Thus, arthritis constitutes a significant public health burden.

While significant therapeutic advances have been made in targeting inflammation in patients with rheumatoid arthritis [Feldmann and Maini, 2008; Siddiqui, 2007], few therapies are available to treat refractory pain and functional limitation in patients with osteoarthritis. Use of common therapies such as nonsteroidal anti-inflammatory drugs (NSAIDs), opioid medications and analgesics is associated with significant adverse events in some patients [Zhang et al. 2008, 2007; Ge et al. 2006]. Intra-articular corticosteroids, intra-articular hyaluronic acid and topical preparations have limited efficacy in patients with osteoarthritis [Bellamy et al. 2006a, 2006b; Van Der Windt et al. 2003; Green et al. 2003; Rains and Bryson, 1995]. Physical therapy is effective [Jamtvedt et al. 2008]; however, compliance with therapy has not been assessed and many patients are unable to pursue the therapy due to personal preference, comorbidities and/or distance from the therapy site. Thus, limited effective and safe therapeutic options are available for the treatment of refractory joint pain in patients with arthritis. There is a need therefore for new therapeutic options for treatment of refractory osteoarticular pain.

Botulinum toxin (BoNT) is one of the most potent neurotoxins. It exists in seven serotypes, A through G. It consists of a 50KDa light chain and a 100 KDa heavy chain linked with a disulfide bond. Most clinical applications of BoNTare based on its ability to block neuromuscular transmission by blocking the release of acetylcholine [Arnon et al. 2001], which leads to reversible muscle paralysis. However, in several clinical studies, including those of treatment of painful muscle contractions in patients with cervical dystonia [Sycha et al. 2004; Jankovic and Schwartz, 1990] and migraine/tension headaches [Gobel et al. 2001], an independent antinociceptive action was noted [Freund and Schwartz, 2003; Aoki, 2003]. The onset of muscle pain relief after muscular injection of BoNT occurred sooner than relief of muscle spasm; it outweighed and often lasted longer than the relief of muscle spasm, thereby suggesting a different antinociceptive action [Sycha et al. 2004; Freund and Schwarz, 2003]. This led to investigation of BoNT as a treatment for headaches, with many randomized controlled trials (RCTs) underway.

In this evidence-based review, the evidence from nonhuman studies and the clinical observations from nonmusculoskeletal application in human studies supporting an antinociceptive action of BoNT are summarized. A systematic review of published nonrandomized (prospective and retrospective cohort studies and case series) and randomized studies of BoNT for osteoarticular pain was then undertaken by performing Pubmed searches for various musculoskeletal pain conditions and BoNT. Case reports were not included in this review. Myofascial pain syndromes were not included in this review, since they have been the focus of previous reviews [Ho and Tan, 2007; Cuevas-Trisan and Cruz-Jimenez, 2006].

Role of neuropeptides in chronic joint pain and effect of botulinum toxin on neuropeptides

Recent reviews summarize our current understanding of joint pain and various mechanisms contributing to it [Schaible et al. 2009, 2006]. The joints are innervated with articular nerves that contain A-delta, A-beta and C-fibers. All joint structures except articular cartilage have these nerve endings. In normal healthy individuals, these nociceptors have a high threshold for excitation in response to mechanical and thermal stimuli, such that normal activities of walking, stair climbing, sports, and palpation of the joint are not associated with pain/unpleasant sensation. However, in the presence of joint injury or inflammation, the excitation threshold of many of these nerve fibers is decreased. This leads to enhanced responses to both innocuous and noxious mechanical, chemical and thermal stimuli. This phenomenon is called peripheral sensitization [Schaible et al. 2009]. Chronic joint inflammation is also associated with hyperexcitability of spinal nociceptive neurons, ie central sensitization [Neugebauer et al. 1993; Schaible et al. 1987]. A variety of mediators can sensitize joint nerves and nociceptors to mechanical stimuli including bradykinin, prostaglandin E2, prostaglandin I2, serotonin, substance P (SP) and neuropeptide Y [Schaible et al. 2006]. Another contributor to joint pain and inflammation is neurogenic inflammation. Articular nerves stimulated due to inflammation in arthritis release neuropeptides from nerve terminals as a result of axon reflexes. Postganglionic sympathetic nerves release neuropeptides due to sympathetic reflexes, and local inflammatory cells release neuropeptides due to cytokine or neuropeptide-stimulation [Schaible et al. 2005]. It is likely that these processes underlie the clinical observed signs and symptoms of pain and mechanical hyperalgesia in inflamed joints.

Activation of glial cells, other immune cells, cytokines and neuropeptides contributes to the generation of pain [Watkins et al. 2003; Watkins and Maier, 2003, 2002; Woolf et al. 1997, 1994; Woolf and Weisfeld-Hallin, 1986]. Pain pathways, pain receptors and various contributors to both inflammatory and neuropathic pain have been summarized in recent studies and reviews [Woolf, 2004; Woolf and Mannion, 1999; Woolf and Decosterd, 1999; Woolf and Costigan, 1999; Willis and Westlund, 1997; Jones, 1991].

BoNT has been shown to interfere with expression of various neuropeptides such as SP and calcitonin gene-related protein (CGRP), which are key mediators of neurogenic inflammation [Birklein and Schmelz, 2008]. In an animal model of botulinum toxin A (BoNT/A), injections into rat paws reduced formalin-induced paw edema, tissue glutamate release and spinal cord electrical excitations [Cui et al. 2004]. BoNT/A inhibited stimulated SP release [Lucioni et al. 2008; Purkiss et al. 2000] and CGRP release [Lucioni et al. 2008; Rapp et al. 2006; Durham et al. 2004] in models of acute and chronic inflammation. In vitro studies showed that BoNT/A inhibited stimulated CGRP release from rat trigeminal ganglia [Meng et al. 2007] and capsaicin-stimulated SP release from embryonic rat dorsal root ganglia neurons [Purkiss et al. 2000]. In particular, BoNT have been shown to inhibit cytokines, neuropeptides and other inflammatory mediators that play an important role in pathophysiology of both rheumatoid arthritis and rat adjuvant arthritis (animal model similar to human rheumatoid arthritis) [Ahmed et al. 1995; Larsson et al. 1991; Kar et al. 1991; Devillier et al. 1986]. Thus, there is preclinical evidence suggesting an antinociceptive mechanism of action of BoNT.

Clinical observations suggesting antinociceptive action of botulinum toxin

Various clinical studies support the antinociceptive action of BoNT [Yuan et al. 2009; Patti et al. 2008; Kramer et al. 2003], while some studies found no such evidence [Sycha et al. 2006; Voller et al. 2003; Blersch et al. 2002].

Kramer and colleagues studied the effect of intra-dermal injection of 5–20 mouse units of BoNT/A or placebo in a RCT in 15 healthy volunteers, followed up for 14 days [Kramer et al. 2003]. Transcutaneous electrical stimulation was used to produce pain, hyperalgesia and neurogenic flare. BoNT/A caused an anhidrotic skin area in all cases, and had a significantly smaller axon reflex flare, lower pain rating, but similar amount of hyperalgesia to pinprick and allodynia after electrical stimulation, as compared to placebo. This study suggested that BoNT/A reduces peripheral neuropeptide release, but the evidence for a direct analgesic effect was limited.

Yuan and colleagues performed a double-blind crossover trial of intradermal BoNT/A for diabetic neuropathic pain in 18 patients [Yuan et al. 2009]. There was a significant reduction in visual analog scale (VAS) pain by 0.83 at 1 week, 2.22 at 4 weeks, 2.33 at 8 weeks, and 2.53 at 12 weeks after injection in the BoNT/A group, as compared to the respective changes of 0.39, −0.11, 0.42, and 0.53 for the placebo group at the same time points (p < 0.05). Within the BoNT/A group, 44.4% of the participants experienced a reduction in VAS of 3 or more within 3 months of injection, whereas there was no similar response in the placebo group.

Patti and colleagues studied 30 patients with thrombosed external hemorrhoids who did not desire surgery [Patti et al. 2008]. Patients were randomized to a single intrasphincteric injection of 30 units of BoNT or saline. After 5 days of treatment, the maximum resting pressure on anal manometry fell more significantly in the BoNT group (p = 0.004). The reduction in pain intensity with BoNT was noted within 1 day of injection (p < 0.001).

Ranoux and colleagues performed a RCT of single intradermal injection of 20–190 units of BoNT/A into the painful area in 29 patients with focal painful neuropathies and mechanical allodynia [Ranoux et al. 2008]. Patients were followed for 24 weeks. BoNT/A injections were associated with persistent sustained effects on spontaneous pain intensity, neuropathic symptoms, and general activity from 2 weeks after the injection to 14 weeks, compared to placebo.

In a randomized, double-blind study, Sycha et al. compared a single intracutaneous injection of BoNT/A 100 units to placebo in six healthy volunteers using a human acute inflammatory skin model with ultraviolet B radiation induced sunburn [Sycha et al. 2006]. No significant differences were noted between the groups in heat or cold pain perception threshold, skin blood flow, mechanical pain threshold or mechanical allodynia. BoNT/A produced changes in sudomotor function. The sample size in this study was very small, leading to a possibility of type II error, ie failure to notice a difference when one truly exists. Blersch and colleagues compared the heat and cold thresholds in 50 healthy volunteers who were each injected with BoNT/A 100 units or placebo in the two forearms in a double-blind fashion [Blersch et al. 2002]. Using quantitative sensory testing, no differences were found between the groups with regards to heat and cold pain thresholds at 4 and 8 weeks. In addition, no differences were found in electric stimulation pain thresholds between the groups. This study suggested that there was no evidence of direct antinociceptive effect of BoNT/A in this skin model of nociception, and that antinociceptive action may be secondary to other effects of BoNT/A such as chemodenervation or anti-inflammatory effects.

Voller and colleagues studied 16 healthy volunteers after injection of either 30 units of BoNT/A or placebo intracutaneously and responses were studied up to 28 days after the injection and after capsaicin application at 28 days [Voller et al. 2003]. The groups did not differ significantly in any of the following outcomes at day 28: heat pain perception and tolerance thresholds; electric pain perception and tolerance thresholds; area of secondary hyperalgesia after capsaicin application; and for the capsaicin-induced flare.

Open-label studies of botulinum toxin in osteoarticular pain

Refractory joint pain

In a retrospective study, we reported the results of intra-articular injection of 25–100 units of BoNT/A in 15 refractory painful shoulder and lower extremity joints in 11 patients [Mahowald et al. 2006]. There were nine women and two men with age ranging from 42 to 82 years. A clinically and statistically significant decrease in pain severity and improvement in function was noted from baseline: lower extremity and shoulder pain decreased from 7 to 2.7 and 8.2 to 2.4, respectively; shoulder flexion and abduction improved from 68 to 113 degrees and 50 to 74 degrees, respectively; and timed stands test (time to stand up 10 times from a sitting position) improved from 36 to 23 seconds. The duration of relief/improvement lasted 3–10 months, and relief began by 2 weeks in most patients. None of the patients experienced any adverse event.

In long-term follow-up of these 15 joints in 11 patients, 10 joints were reinjected with 30–150 units of BoNT/A intra-articularly (Botox, Allergan, Irvine, California, USA) [Singh et al. 2009a]. Nine of the 10 reinjections were associated with pain reduction, as seen with the first injection. Reduction in pain severity from 6.6 (SD, 1.2) to 3.3 (SD, 2.7) lasting 3–17 months was noted, which was statistically significant (p = 0.003). None of the patients experienced any systemic adverse event related to BoNT One patient had increased joint swelling with no increase in joint pain 3 weeks after BoNT injection. Another patient had continued increase in joint pain after BoNT injection, which was relieved with a subsequent BoNT injection.

In another case series, 11 adults with refractory pain underwent injection of BoNT type A (25–100 units; Botox, Allergan) or type B (5000 units; Myobloc, Solstice Neurosciences, San Francisco, California, USA) into sacroiliac, cervical/lumbar facet or sternoclavicular joint joints and C-2 roots and lumbar disc [Dykstra et al. 2007]. There were nine women and two men with mean age of 48 years (SD, 10 years; range, 32–68 years). Median pain scores decreased significantly after botulinum toxin injections, with median decrease of 3 on 0–10 pain scale (range, 0–5; p = 0.008). Pain decrease began within 3–5 days for patients who responded. Three patients had no change in pain severity after BoNT injections, while eight had a decrease. Five patients received repeat injections with no evidence of decreasing efficacy of pain relief with BoNT injections; in fact, the duration of pain relief increased with each successive treatment for four of the five patients having multiple treatments. Median duration of pain relief with BoNT injections was 1.6 months longer than that seen with corticosteroid injections. No adverse events were reported by the patients.

Tennis elbow

In an open-label case series of 14 patients with ‘treatment-resistant’ tennis elbow, 20–40 units of BoNT/A were injected into the extensor digitorum communis, Moore and colleagues found > 50% pain relief in nine of 14 patients, and complete pain relief in four of 14 patients during the 6–8 month follow-up [Morre et al. 1997]. Pain relief began by 2 weeks in 10 patients, 3 weeks in one and after 1 month in two patients.

Temporomandibular joint pain

In an open-label study of 41 patients with painful hyperactivity of the masticatory muscles, 200 units of BoNT/A (Dysport, Ipsen, Slough, UK) was injected on either side under electromyographic guidance and patients observed for up to 12 months [Von Lindern, 2001]. 80% patients had improvement in pain; pain severity decreased from a mean of 6.4 to 3.5 and 13 patients had a ‘major improvement’ as evident by disappearance of pain. Relief lasted 3–12 months during the observation period for most; only seven patients requested reinjection. One patient had temporary speech impairment and swallowing difficulty postinjection. In an open-label study, 46 patients with TMD for a median duration of 96 months were injected with 150 units of BoNT A in both massager and temporal is muscles and followed up to 8 weeks [Freund et al. 2000]. A significant improvement was noted in pain VAS, functional index, tenderness to palpation and interincisal oral opening.

Anterior knee pain

Singer and colleagues injected 300–500 units of BoNT/A (Dysport) into vastus lateralis muscles followed by a 12 week home exercise program to strengthen vastus medialis in eight female patients with chronic anterior knee pain of longer than 6 months that had failed conservative management [Singer et al. 2006]. Patients reported decreased knee pain, increased function and had an improvement in the time taken to ascend and descend a flight of 11 stairs from 12 to 10 seconds; improvements that were maintained at 24 weeks.

Low back pain

Ney and colleagues reported the results of injection of 200–500 units of BoNT/A intra-muscularly from L2 to S1 in 60 patients with chronic low back pain of 9-year mean disease duration in an open-label prospective study [Ney et al. 2006]. Response as defined by the occurrence of two of three of the following criteria: ≥ 50% improvement in pain VAS, ≥ 2 grade improvement in pain and functional subsets of Oswestry Low Back Pain Questionnaire, and ≥ 30% improvement in number of pain days from baseline. At 2 months 58% patients responded, with 17% still showed improvement at 4 months of follow-up.

Plantar fasciitis

Placzek and colleagues reported 1 year follow-up of a case series of nine patients with chronic plantar fasciitis, who were injected with 200 units of BoNT/A (Dysport). Statistically significant pain relief began 2 weeks after the injection (pain scale, 0–10, 4.2–1.9, p = 0.012) and persisted until 52 weeks (pain scale, 0–10, 4.2–0.4, p = 0.043) [Placzek et al. 2005].

Randomized controlled trials of botulinum toxin in osteoarticular pain

Tennis elbow

In a study by Hayton and colleagues 40 patients with refractory painful tennis elbow with pain lasting more than 6 months, who had failed treatment with one or more corticosteroid injections and a full course of physiotherapy were randomized to 50 units of BoNT/A (Allergan) or normal saline placebo (2ml) 5cm distal to the area of maximal tenderness at the lateral epicondyle (Tables 1 and and2)2) [Hayton et al. 2005]. There were no statistically significant differences between BoNT and placebo groups at 3 months after the injection in pain, grip strength or quality of life measured by Short-Form 12 physical and mental component summary scores.

Table 1.
Summary of studies of botulinum toxin in osteoarticular pain-efficacy outcomes.
Table 2.
Safety outcomes from randomized studies of botulinum toxin use in osteoarticular pain.

In another study by Wong and colleagues (Tables 1 and and2),2), 60 patients with painful tennis elbow for 3 months or longer were randomized to either a single injection of 60 units of BoNT/A (Dysport; Ipsen) or placebo and followed for 12 weeks in a double-blinded multicenter study [Wong et al. 2005]. Patients were treatment-naïve with no prior local acupuncture therapy for their tennis elbow. Pain on a VAS (0–100 mm) scale decreased significantly more in the active treatment group (65.5 at baseline to 25.3 at week 4 and 23.5 at week 12) than placebo (66.2 at baseline to 50.5 at week 4 and 43.5 at week 12). The differences between groups were statistically significant at both week 4 (p < 0.001) and week 12 (p = 0.006). Although four patients in the botulinum group had paresis of the fingers at 4 weeks (in one patient it persisted to week 12) compared to none in the placebo group, the grip strength was similar in both groups at the two time points. A small sample and short follow-up period are the limitations of the study. These two studies differed in patient population (all patients versus those with refractory disease), duration of disease (> 3 months versus >6 months), site of injection (1cm versus 5 cm from the lateral epicondyle) and the preparation used [60 units of Dysport (Ipsen Pharmaceuticals) versus 50 units of Botox (Allergan Pharmaceuticals)].

Another randomized study (Tables 1 and and2)2) compared one or two injections of 30–40 units of BoNT/A (Allergan) with the surgical release of the extensor origin of the extensor carpi radialis brevis tendon in 40 patients with refractory chronic painful tennis elbow (average duration of symptoms ~ 10 months) [Keizer et al. 2002]. They found no differences between the groups with regards to pain and grip strength up to 2 years of follow-up, while minor differences were noted at shorter follow-up periods. A limitation of the study was lack of description of outcomes, no a priori designation of outcomes as primary versus secondary and use of nonvalidated outcomes.

Facial pain and temporomandibular disorder

Temporomandibular disorder is a group of pathologic conditions affecting the temporomandibular joint, its associated structures and its functions. In a single-blinded, randomized study of 90 patients with chronic facial pain caused by hyperactivity of masticatory muscles, who had failed conservative treatment, received intramuscular injections of 35 mouse units of BoNT/A (Allergan; n = 60) or placebo (n = 30) on each side of the masticatory muscle (Tables 1 and and2)2) [Von Lindern et al. 2003]. A significantly greater reduction of 0–10 VAS pain was noted in the botulinum toxin (3.2 units) versus placebo group (0.4 units) (p < 0.01; at follow-up between 1 and 3 months). A greater proportion of patients in BoNT/A compared to the placebo group had ≥2-point improvement in VAS pain during the follow-up (Table 1). This study has many limitations: blinding was not described (patient or physician blinded single-blind), the outcome measurement time-point was not described, and the study had a very short follow-up duration.

Low back pain

Foster and colleagues compared 200 units of BoNT/A (Allergan) injected intramuscular para-vertebrally from L1–5/L2-S1 (n = 15) to placebo (n = 16) in 31 patients with chronic back pain of ≥ 6 month duration (Table 1) [Foster et al. 2001]. Pain relief exceeding 50% on VAS was significantly higher in Botox versus placebo group, respectively: 73% versus 25% at 3 weeks, and 60% versus 13% at 8 weeks (Table 1). The Oswestry Low Back Pain Questionnaire score improved in significantly more patients in Botox versus placebo group. A small sample size is a limitation of this study.

Refractory shoulder joint pain

Singh and colleagues injected 100 units of BoNT/A (Allergan Pharmaceuticals) into glenohumeral (shoulder) joints of patients with osteoarthritis or rheumatoid arthritis related refractory, chronic shoulder joint pain due to osteoarthritis or rheumatoid arthritis, who had all failed conservative management with intra-articular corticosteroids and oral medications (Tables 1 and and2)2) [Singh et al. 2009b].

Hand pain and carpal tunnel syndrome

Breuer and colleagues randomized 20 patients with carpal tunnel syndrome with hand pain to receive electromyographically-guided placebo or botulinum toxin type B injections in three hypothenar muscles anatomically attached to the carpal tunnel (Tables 1 and and22) [Breuer et al. 2006]. During the 13-week trial, significant decrease in pain outcomes and improvement in function were noted in both placebo and the BoNT/A groups compared to the baseline, but there were no significant differences between the two groups. A small sample size, unblinding of the first two patients and variation in the BoNT/A dose during the trial were the limitations of this study.

Heel pain and plantar fasciitis

Babcock and colleagues compared 70 units of BoNT/A injected into plantar fascia compared to a placebo injection in 27 patients (43 feet) with chronic refractory plantar fasciitis for ≥6 months, that had failed all conservative strategies except surgery or extracorporeal shock therapy (Tables 1 and and2)2) [Babcock et al. 2005]. Compared to the placebo group, botulinum group improved significantly more pain relief on a VAS (4.75 versus 0.6 at 3 weeks and 4.95 versus 1.2 at 8 weeks, p < 0.005 for both; 0–10 cm scale), significantly lower VAS pain, and significantly better foot function as assessed by the Maryland Foot Score and less muscle tenderness at plantar fascia insertion as assessed by pressure algometry response at both 3 and 8 weeks follow-up.

Summary and conclusions

In this paper, studies of use of BoNT for osteoarticular pain are reviewed. Preclinical laboratory evidence and clinical evidence emerging from use of BoNT for other applications suggests an independent antinociceptive mechanism of action. While there are several osteoarticular conditions for which BoNT had been studied in an RCT compared to placebo, for most conditions there was a single RCT. These studies had several limitations. Most studies were single center, had a small sample size, short follow-up and in some cases, nonstandardized injection techniques. Observation of larger effect size in uncontrolled studies (retrospective and prospective) as compared to controlled trials indicates bias and placebo effect, as reported previously for other conditions. The evidence for an antinociceptive action of BoNT in osteoarticular pain is growing. Larger multicenter studies of longer duration that test various doses, regimens and routes of administration of BoNT are needed to better define its role in management of osteoarticular pain.

Footnotes

Grant Support: Supported by NIH CTSA Award 1 KL2 RR024151–01 (Mayo Clinic Center for Clinical and Translational Research).

References

  • Ahmed M., Bjurholm A., Schultzberg M., Theodorsson E., Kreicbergs A. (1995) Increased levels of substance P and calcitonin gene-related peptide in rat adjuvant arthritis. A combined immunohistochemical and radioimmunoassay analysis. Arthritis Rheum 38: 699–709. [PubMed]
  • Aoki K.R. (2003) Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache 43(Suppl 1): S9–15. [PubMed]
  • Arnon S.S., Schechter R., Inglesby T.V., Henderson D.A., Bartlett J. G., Ascher M. S., et al. (2001) Botulinum toxin as a biological weapon: medical and public health management. JAMA 285: 1059–1070. [PubMed]
  • Babcock M.S., Foster L., Pasquina P., Jabbari B. (2005) Treatment of pain attributed to plantar fasciitis with botulinum toxin A: a short-term, randomized, placebo-controlled, double-blind study. Am J Phys Med Rehabil 84: 649–654. [PubMed]
  • Bellamy N., Campbell J., Robinson V., Gee T., Bourne R., Wells G. (2006a) Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst RevCD005328. [PubMed]
  • Bellamy N., Campbell J., Robinson V., Gee T., Bourne R., Wells G. (2006b) Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst RevCD005321. [PubMed]
  • Birklein F., Schmelz M. (2008) Neuropeptides, Neurogenic inflammation and complex regional pain syndrome (CRPS). Neurosci Lett 437: 199–202. [PubMed]
  • Bjork M.A., Thyberg I.S., Skogh T., Gerdle B.U. (2007) Hand function and activity limitation according to health assessment questionnaire in patients with rheumatoid arthritis and healthy referents: 5-year follow-up of predictors of activity limitation (the Swedish Tira Project). J Rheumatol 34: 296–302. [PubMed]
  • Blersch W., Schulte-Mattler W.J., Przywara S., May A., Bigalke H., Wohlfarth K. (2002) Botulinum toxin A and the cutaneous nociception in humans: a prospective, double-blind, placebo-controlled, randomized study. J Neurol Sci 205: 59–63. [PubMed]
  • Breivik H., Collett B., Ventafridda V., Cohen R., Gallacher D. (2006) Survey of chronic pain in europe: prevalence, impact on daily life, and treatment. Eur J Pain 10: 287–333. [PubMed]
  • Breuer B., Siperber K., Wallenstein S., Kiprovski K., Calapa A., Snow B., et al. (2006) Clinically significant placebo analgesic response in a pilot trial of botulinum B in patients with hand pain and carpal tunnel syndrome. Pain Med 7: 16–24. [PubMed]
  • Centers for Disease Control and Prevention (CDC) (2009) Prevalence and most common causes of disability among adults–United States, 2005. MMWR Morb Mortal Wkly Rep 58: 421–426. [PubMed]
  • Cuevas-Trisan R.L., Cruz-Jimenez M. (2006) The use of botulinum toxin in physical medicine and rehabilitation. Bol Asoc Med P R 98: 42–55. [PubMed]
  • Cui M., Khanijou S., Rubino J., Aoki K.R. (2004) Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 107: 125–133. [PubMed]
  • Devillier P., Weill B., Renoux M., Menkes C., Pradelles P. (1986) Elevated levels of tachykinin-like immunoreactivity in joint fluids from patients with rheumatic inflammatory diseases. N Engl J Med 314: 1323. [PubMed]
  • Durham P.L., Cady R., Cady R. (2004) Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache 44: 35–42, discussion 42–33. [PubMed]
  • Dykstra D., Stuckey M.W., Schimpff S.N., Singh J.A., Mahowald M.L. (2007) The effects of intra-articular botulinum toxin on sacroiliac, cervical/lumbar facet and sterno-calvicular joint pain and C-2 root and lumbar disc pain: a case series of 11 patients. The Pain Clinic 19: 27–32.
  • Feldmann M., Maini S.R. (2008) Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics. Immunol Rev 223: 7–19. [PubMed]
  • Foster L., Clapp L., Erickson M., Jabbari B. (2001) Botulinum toxin A and chronic low back pain: a randomized, double-blind study. Neurology 56: 1290–1293. [PubMed]
  • Freund B., Schwartz M. (2003) Temporal relationship of muscle weakness and pain reduction in subjects treated with botulinum toxin A. J Pain 4: 159–165. [PubMed]
  • Freund B., Schwartz M., Symington J.M. (2000) Botulinum toxin: new treatment for temporomandibular disorders. Br J Oral Maxillofac Surg 38: 466–471. [PubMed]
  • Ge Z., Hu Y., Heng B.C., Yang Z., Ouyang H, Lee E.H., et al. (2006) Osteoarthritis and therapy. Arthritis Rheum 55: 493–500. [PubMed]
  • Gobel H., Heinze A., Heinze-Kuhn K., Jost W. (2001) Evidence based medicine: botulinum toxin A in migraine and tension type headache. J Neurol 248(Suppl): 34–38. [PubMed]
  • Green S., Buchbinder R., Glazier R., Forbes A. (2003) Interventions for shoulder pain. Cochrane Database Syst Rev.
  • Hayton M.J., Santini A.J., Hughes P.J., Frostick S.P., Trail I.A., Stanley J.K. (2005) Botulinum toxin injection in the treatment of tennis elbow. A double-blind, randomized, controlled, pilot study. J Bone Joint Surg Am 87: 503–507. [PubMed]
  • Ho K.Y., Tan K.H. (2007) Botulinum toxin A for myofascial trigger point injection: a qualitative systematic review. Eur J Pain 11: 519–527. [PubMed]
  • Huijnen B., Van Der Horst F., Van Amelsvoort L., Wesseling G., Lansbergen M., Aarts P., et al. (2006) Dyspnea in elderly family practice patients. [PubMed]
  • Occurrence, severity, quality of life and mortality over an 8-year period. Fam Pract 23: 34–39. [PubMed]
  • Hunter D.J., McDougall J.J., Keefe F.J. (2009) The symptoms of osteoarthritis and the genesis of pain. Med Clin North Am 93: 83–100, xi. [PubMed]
  • Jamtvedt G., Dahm K.T., Christie A., Moe R.H., Haavardsholm E., Holm I., et al. (2008) Physical therapy interventions for patients with osteoarthritis of the knee: an overview of systematic reviews. Phys Ther 88: 123–136. [PubMed]
  • Jankovic J., Schwartz K. (1990) Botulinum toxin injections for cervical dystonia. Neurology 40: 277–280. [PubMed]
  • Jones S.L. (1991) Descending noradrenergic influences on pain. Prog Brain Res 88: 381–394. [PubMed]
  • Kar S., Gibson S.J., Rees R.G., Jura W.G., Brewerton D.A., Polak J.M. (1991) Increased calcitonin gene-related peptide (CGRP), substance P, and enkephalin immunoreactivities in dorsal spinal cord and loss of CGRP-immunoreactive motoneurons in arthritic rats depend on intact peripheral nerve supply. J Mol Neurosci 3: 7–18. [PubMed]
  • Keizer S.B., Rutten H.P., Pilot P., Morre H.H., V Os J.J., Verburg A.D. (2002) Botulinum toxin injection versus surgical treatment for tennis elbow: a randomized pilot study. Clin Orthop Relat Res 125–131. [PubMed]
  • Kramer H.H., Angerer C., Erbguth F., Schmelz M., Birklein F. (2003) Botulinum toxin A reduces neurogenic flare but has almost no effect on pain and hyperalgesia in human skin. J Neurol 250: 188–193. [PubMed]
  • Kvien T.K., Uhlig T. (2005) Quality of life in rheumatoid arthritis. Scand J Rheumatol 34: 333–341. [PubMed]
  • Larsson J., Ekblom A., Henriksson K., Lundeberg T., Theodorsson E. (1991) Concentration of substance P, neurokinin A, calcitonin gene-related peptide, neuropeptide Y and vasoactive intestinal polypeptide in synovial fluid from knee joints in patients suffering from rheumatoid arthritis. Scand J Rheumatol 20: 326–335. [PubMed]
  • Lawrence R.C., Helmick C.G., Arnett F.C., Deyo R.A., Felson D. T., Giannini E. H., et al. (1998) Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 41: 778–799. [PubMed]
  • Layeeque R., Hochberg J., Siegel E., Kunkel K., Kepple J., Henry-Tillman R.S., et al. (2004) Botulinum toxin infiltration for pain control after mastectomy and expander reconstruction. Ann Surg 240: 608–613, discussion 613–614. [PubMed]
  • Lucioni A., Bales G.T., Lotan T.L., McGehee D.S., Cook S.P., Rapp D.E. (2008) Botulinum toxin type A inhibits sensory neuropeptide release in rat bladder models of acute injury and chronic inflammation. BJU Int 101: 366–370. [PubMed]
  • Mahowald M.L., Singh J.A., Dykstra D. (2006) Long term effects of intra-articular botulinum toxin A for refractory joint pain. Neurotox Res 9: 179–188. [PubMed]
  • Meng J., Wang J., Lawrence G., Dolly J.O. (2007) Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential. J Cell Sci 120: 2864–2874. [PubMed]
  • Morre H.H., Keizer S.B., Van Os J.J. (1997) Treatment of chronic tennis elbow with botulinum toxin. Lancet 349: 1746. [PubMed]
  • Neugebauer V., Lucke T., Schaible H.G. (1993) N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists block the hyperexcitability of dorsal horn neurons during development of acute arthritis in rat's knee joint. J Neurophysiol 70: 1365–1377. [PubMed]
  • Ney J.P., Difazio M., Sichani A., Monacci W., Foster L., Jabbari B. (2006) Treatment of chronic low back pain with successive injections of botulinum toxin A over 6 months: a prospective trial of 60 patients. Clin J Pain 22: 363–369. [PubMed]
  • Patti R., Arcara M., Bonventre S., Sammartano S., Sparacello M., Vitello G., et al. (2008) Randomized clinical trial of botulinum toxin injection for pain relief in patients with thrombosed external haemorrhoids. Br J Surg 95: 1339–1343. [PubMed]
  • Placzek R., Deuretzbacher G., Buttgereit F., Meiss A.L. (2005) Treatment of chronic plantar fasciitis with botulinum toxin A: an open case series with a 1 year follow up. Ann Rheum Dis 64: 1659–1661. [PMC free article] [PubMed]
  • Purkiss J., Welch M., Doward S., Foster K. (2000) Capsaicin-stimulated release of substance P from cultured dorsal root ganglion neurons: involvement of two distinct mechanisms. Biochem Pharmacol 59: 1403–1406. [PubMed]
  • Rains C., Bryson H.M. (1995) Topical capsaicin. A review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging 7: 317–328. [PubMed]
  • Ranoux D., Attal N., Morain F., Bouhassira D. (2008) Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann Neurol 64: 274–283. [PubMed]
  • Rapp D.E., Turk K.W., Bales G.T., Cook S.P. (2006) Botulinum toxin type A inhibits calcitonin gene-related peptide release from isolated rat bladder. J Urol 175: 1138–1142. [PubMed]
  • Salaffi F., Carotti M., Stancati A., Grassi W. (2005) Health-related quality of life in older adults with symptomatic hip and knee osteoarthritis: a comparison with matched healthy controls. Aging Clin Exp Res 17: 255–263. [PubMed]
  • Schaible H.G., Schmidt R.F., Willis WD. (1987) Enhancement of the responses of ascending tract cells in the cat spinal cord by acute inflammation of the knee joint. Exp Brain Res 66: 489–499. [PubMed]
  • Schaible H.G., Del Rosso A., Matucci-Cerinic M. (2005) Neurogenic aspects of inflammation. Rheum Dis Clin North Am 31: 77–101, ix. [PubMed]
  • Schaible H.G., Schmelz M., Tegeder I. (2006) Pathophysiology and treatment of pain in joint disease. Adv Drug Deliv Rev 58: 323–342. [PubMed]
  • Schaible H.G., Richter F., Ebersberger A., Boettger M.K., Vanegas H., Natura G., et al. (2009) Joint pain. Exp Brain Res 196: 153–162. [PubMed]
  • Siddiqui MA. (2007) The efficacy and tolerability of newer biologics in rheumatoid arthritis: best current evidence. Curr Opin Rheumatol 19: 308–313. [PubMed]
  • Singer B.J., Silbert P.L., Dunne J.W., Song S., Singer K.P. (2006) An open label pilot investigation of the efficacy of botulinum toxin type A [Dysport] injection in the rehabilitation of chronic anterior knee pain. Disabil Rehabil 28: 707–713. [PubMed]
  • Singh J.A., Mahowald M.L., Kushnaryov A., Goelz E., Dykstra D. (2009) Repeat Injections of intra-articular botulinum toxin A for the treatment of chronic arthritis joint pain. J Clin Rheumatol 15: 35–38. [PubMed]
  • Singh J.A., Mahowald M.L., Noorbaloochi S. (2009) Intra-articular botulinum toxin A for refractory shoulder pain: a randomized, double-blinded, placebo-controlled trial. Transl Res 153: 205–216. [PubMed]
  • Slatkowsky-Christensen B., Mowinckel P., Loge J.H., Kvien T.K. (2007) Health-related quality of life in women with symptomatic hand osteoarthritis: a comparison with rheumatoid arthritis patients, healthy controls, and normative data. Arthritis Rheum 57: 1404–1409. [PubMed]
  • Sycha T., Kranz G., Auff E., Schnider P. (2004) Botulinum toxin in the treatment of rare head and neck pain syndromes: a systematic review of the literature. J Neurol 251(Suppl 1): I19–30. [PubMed]
  • Sycha T., Samal D., Chizh B., Lehr S., Gustorff B., Schnider P., et al. (2006) A lack of antinociceptive or antiinflammatory effect of botulinum toxin A in an inflammatory human pain model. Anesth Analg 102: 509–516. [PubMed]
  • Van Der Windt D.A., Bouter L.M. (2003) Physiotherapy or corticosteroid injection for shoulder pain? Ann Rheum Dis 62: 385–387. [PMC free article] [PubMed]
  • Voller B., Sycha T., Gustorff B., Schmetterer L., Lehr S., Eichler H. G., et al. (2003) A randomized, double-blind, placebo controlled study on analgesic effects of botulinum toxin A. Neurology 61: 940–944. [PubMed]
  • Von Lindern J.J. (2001) Type A botulinum toxin in the treatment of chronic facial pain associated with temporo-mandibular dysfunction. Acta Neurol Belg 101: 39–41. [PubMed]
  • Von Lindern J.J., Niederhagen B., Berge S., Appel T. (2003) Type A botulinum toxin in the treatment of chronic facial pain associated with masticatory hyperactivity. J Oral Maxillofac Surg 61: 774–778. [PubMed]
  • Watkins L.R., Maier S.F. (2002) Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 82: 981–1011. [PubMed]
  • Watkins L.R., Maier S.F. (2003) Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2: 973–985. [PubMed]
  • Watkins L.R., Milligan E.D., Maier S.F. (2003) Glial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain. Adv Exp Med Biol 521: 1–21. [PubMed]
  • Willis WD, Westlund K.N. (1997) Neuroanatomy of the pain system and of the pathways that modulate pain. J Clin Neurophysiol 14: 2–31. [PubMed]
  • Wong S.M., Hui A.C., Tong P.Y., Poon D.W., Yu E., Wong L.K. (2005) Treatment of lateral epicondylitis with botulinum toxin: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 143: 793–797. [PubMed]
  • Woolf C.J. (2004) Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 140: 441–451. [PubMed]
  • Woolf C.J., Costigan M. (1999) Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci USA 96: 7723–7730. [PubMed]
  • Woolf C.J., Decosterd I. (1999) Implications of recent advances in the understanding of pain pathophysiology for the assessment of pain in patients. Pain Suppl 6: S141–147. [PubMed]
  • Woolf C.J., Mannion R.J. (1999) Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353: 1959–1964. [PubMed]
  • Woolf C., Wiesenfeld-Hallin Z. (1986) Substance P and calcitonin gene-related peptide synergistically modulate the gain of the nociceptive flexor withdrawal reflex in the rat. Neurosci Lett 66: 226–230. [PubMed]
  • Woolf C.J., Safieh-Garabedian B., Ma Q.P., Crilly P., Winter J. (1994) Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience 62: 327–331. [PubMed]
  • Woolf C.J., Allchorne A., Safieh-Garabedian B., Poole S. (1997) Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor alpha. Br J Pharmacol 121: 417–424. [PubMed]
  • Yuan R.Y., Sheu J.J., Yu J.M., Chen W.T., Tseng I. J., Chang H. H., et al. (2009) Botulinum toxin for diabetic neuropathic pain: a randomized double-blind crossover trial. Neurology 72: 1473–1478. [PubMed]
  • Zhang W., Moskowitz R.W., Nuki G., Abramson S., Altman R. D., Arden N., et al. (2007) Oarsi recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence. Osteoarthritis Cartilage 15: 981–1000. [PubMed]
  • Zhang W., Moskowitz R.W., Nuki G., Abramson S., Altman R. D., Arden N., et al. (2008) Oarsi recommendations for the management of hip and knee osteoarthritis, part II: oarsi evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 16: 137–162. [PubMed]

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