The use of skeletal muscle relaxants in musculoskeletal injuries: what is the evidence?

Skeletal muscle relaxants (SMRs) consist of a heterogeneous group of medications with a side effect profile of concern. The aim of this paper was to review the evidence of use of SMRs in the treatment of sports injuries. A literature search between 2005 – 2018 (Ovid MEDLINE, SPORTDiscus and SCOPUS) were conducted. In addition, citations within articles were searched, and the most commonly prescribed SMRs in South Africa were also used to explore the literature for additional publications. Relevant studies that met the inclusion criteria were selected. Clinical recommendations for general practitioners are given based on the Strength of Recommendation Taxonomy (SORT) level of evidence. Combination drugs rather than single agents are mostly used, however the effectiveness of SMR agents, single and in combination, as well as its significance as opposed to analgesics and non-steroidal anti-inflammatory drugs, still has to be evaluated. Evidence suggest SMRs to be probably effective for use in non-specific lower back pain (acute and chronic lower back muscle strains, ligament sprains, soft tissue contusions), as well as for whiplash associated disorder, mechanical neck disorders, piriformis syndrome, lateral epicondylosis, and plantar fasciitis. It does not appear if there is a role for SMRs as part of combination management for acute cervical strains, post-exercise muscle soreness or myofacial pain syndrome. However, substantial evidence to confirm the use of SMRs in the treatment of sports injuries have not been adequately investigated and is currently largely based on case reports and general reviews.


Introduction
The escalation and interest in the range of elite and recreational sports participation over the last years lead to the number and variety of injuries sustained to increase concomitantly. [1][2][3] Regardless of increased emphasis on injury prevention in sports by way of awareness, better conditioning and specific preventative measures, injury occurrence remains a problem. 4 The focus of treatment of such an injury is to facilitate the safe return to sports, reducing the risk of re-occurrence of an injury while alleviating psychological stress and promoting health. 4 The treatment of a sports injury aims to reduce pain, swelling, inflammation, and muscle spasm associated with injury, as well as facilitating restoration of function and return to sports. 4 Treatment modalities that may affect tissue healing include non-pharmacological procedures such as the POLICE principle (Protect, Optimal Load, Ice, Compress, Elevate) and physiotherapy modalities, as well as pharmacological management (analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids and skeletal muscle relaxants). The choice of the preferred modality used may differ when treating an acute injury as opposed to a chronic injury. Some of these modalities are established and have been used widely, but many novel treatment modalities are gaining favour (Table 1). the aim of this paper is to review the role that SMRs play in the management of sports injuries.

Spasticity vs. spasm:
Spasticity and spasms are two distinct aetiologies and responds differently to certain medications. Antispasmodics and antispasticity agents are generally not interchangeable. Spasticity is a motor neuron disorder that manifests as a continuous muscle spasm that results in increased muscle tone and stiffness. Muscle spasms are involuntary localised contractions of a muscle or muscle group that causes pain. The exact relationship between the pain and muscle spasm is not well understood and the cycle of pain-spasm-pain is not strongly supported by scientific evidence. Studies report that pain have a tendency to inhibit rather than facilitate voluntary reflex contractile function. [30][31][32][33][34]

Sports injury:
In the recent consensus statement on pain management in elite athletes by the International Olympic Committee, a sports injury is defined as a new or recurring musculoskeletal complaint incurred during competition or training that require medical attention, regardless of the potential absence from competition or training. 35 Engebretsen et al. 36 have previously suggested the definition of a sports injury should require restricted activity for at least one day.
Sports injuries can occur in very different ways and our understanding thereof has increased in recent years. Acute injuries occur as a result of a single-impact macrotrauma, such as a sudden ankle sprain, joint dislocation, or ruptured tendons caused by a single traumatic or forceful blow or event. Overuse (also referred to as chronic) injuries occur as a result of repetitive microtrauma caused by frequent, repeated injury of muscles, tendons, ligaments, joints, and bones. A persisting or constantly recurring injury that may involve a variety of tissues at a number of different sites. Acute on chronic injury is an acute exacerbation of a chronic condition. These basic mechanisms of injury or a combination thereof, can produce injury in any part of the body and are responsible for all sports injuries. 4

Acute vs. chronic pain:
Pain associated with any sport injury is classified as acute (pain duration up to 6 weeks), subacute (pain duration between 6-12 weeks) or chronic (pain duration of 3 months or longer). 35,37 Acute and chronic pain are different clinical entities. Acute pain is provoked by a specific disease or injury, it serves a useful biologic purpose, is associated with skeletal muscle spasm and sympathetic nervous system activation and is self-limited.
Chronic pain, in contrast, may be considered a disease state. It is pain that outlasts the normal time of healing, if associated with a disease or injury. Chronic pain may arise from psychological states, serves no biologic purpose, and has no recognizable endpoint. 38

Sprain vs. strain:
A sprain is a stretch, or a tear of a ligament caused by direct or indirect trauma. A strain is a pull or a tear of a muscle or tendon caused by direct, forceful contact, excessive muscle contraction or overstretching (acute), or monotonous repetitive movement (chronic). 39

Background information on management of musculoskeletal injuries
Wellbeing is a patient's main concern, however a culture of risk is deeply embedded in sports tradition. It is well recognised that in the management of acute pain in those athletes restricted from same-day return to play (RTP), medications should not be prescribed as a stand-alone treatment. It remains essential to identify the injury and the cause of pain and to include other non-pharmacological measures. 35 Therefore, the treatment of sports injuries should include both non-pharmacological and pharmacological management.
Non-pharmacologic modalities include the POLICE principle (Protect, Optimal Load, Ice, Compress, Elevate) 5 Traditionally, the healing approach was RICE (Rest, Ice, Compress and Elevate), however inappropriate amounts of resting an injury may cause further tissue damage as it does not allow the body to remodel necessary bony, musculoskeletal or collagenous structures at appropriate times throughout the healing phases, and promoting inactivity as a form of treatment, will result in the body adapting for rest. The short-term use of ice (in combination with paracetamol) will provide an equivalent analgesic effect without serious side effects. Elements of the POLICE principle, and application thereof, may differ in chronic injury where exercise rehabilitation remains the cornerstone of management to regain function. 40 Various physiotherapy modalities are used in the treatment of acute and chronic muscle stiffness and pain. Dry needling, transcutaneous electrical nerve stimulation (TENS), passive stretching, massage, trigger point release and myofascial release have shown to be effective in reducing pressure pain threshold and increase muscle flexibility. [15][16][17] Pharmacologic modalities include the use of NSAIDs or COX-2 inhibitors (celecoxib, rofecoxib, valdecoxib), centrally acting agents (tramadol/acetaminophen), opioids, and oral SMRs. All these agents help to alleviate discomfort associated with pain and muscle spasm. [41][42][43][44][45][46][47][48][49][50] There are few good studies available to guide the rationale for the use of medications in the treatment of acute musculoskeletal injuries. When examining clinical trials, a number of factors complicate evaluation of efficacy of one drug over another in the acute setting. Factors include: inconsistent and vague inclusion criteria, the use of subjective and different clinical end points, varying doses of study drugs, highly different placebo response rates, underpowered trials, poorly clarified non-pharmacologic interventions and inappropriate statistical procedures. [51][52][53] It is thus complicated to generalise the comparative effectiveness of distinctive agents and/or combinations thereof. Furthermore, the majority of acute musculoskeletal conditions are self-limiting by nature, therefore experience in the long-term use of medications for musculoskeletal spasm and pain is quite limited. 53 NSAIDs, COX-2 inhibitors, and muscle relaxants respectively, accounted for 16.3%, 10%, and 18.5% of total prescriptions for back pain in the United States in 2000. Among individual drugs, ibuprofen and naproxen accounted for most of the prescriptions for traditional NSAIDs (60%), whereas two thirds of the prescriptions for muscle relaxants were attributable to cyclobenzaprine, carisoprodol, and methocarbamol. 54 There is some evidence that professional athletes use muscle relaxants and other medications with or without medical advice. Various surveys since 2000 on the trends and use of medication intake by elite male football players prior to international matches, have indicated muscle relaxant usage between second and fourth highest. In many instances various different preparations were taken simultaneously. The number of players taking muscle relaxants increased significantly over the four tournaments (2.2% in the 2000 FIFA Futsal World Cup to 14.3% in the 2012 FIFA Futsal World Cup, < 0.05). This high consumption of medication use in international football raises the questions on whether medication is used for therapeutic reasons only. [55][56][57][58] The use of medication in elite female soccer players, however seems fewer than in adolescent male soccer players during global world contests. 59 The prescription of medications should be consistent with established, recognised pharmacological and pharmacodynamic principles (i.e. the biochemical, physiologic, and molecular effects of drugs on the body). This include the time of onset of action, the effectiveness for pain relief, any potential side effects and complications as well as the route of administration. 35 Administration can be oral, intramuscular, intravenous and/or topical. Physicians, more often than not, recommend or prescribe oral medications for the treatment of acute musculoskeletal pain. 29 In general, acute pain medication should not be used for more than five days. Medication for more severe injuries associated with moderate to severe pain, should be re-evaluated if pain persists beyond 10 days. 35

What is a skeletal muscle relaxant (SMR)?
SMRs consist a diverse group of medications, with structurally unrelated active ingredients, and with varied pharmacologic profiles and side effects. 34 These drugs have been approved to treat two different types of underlying conditions: spasticity from upper motor neuron syndromes and muscular pain or spasms from peripheral musculoskeletal conditions. Spasticity is not covered in this article. SMR drugs used for musculoskeletal injuries are presented in Table 2.
The goal of SMR administration is to reduce skeletal muscle spasm, to assist in pain relief and to increase mobility of affected muscles. 24,39 Pain relief can be affected by either muscle relaxation and/or sedation due to the muscle relaxants. Also more randomised control trials (RCTs) are needed to confirm effectiveness, but from a clinical perspective combination drugs (e.g. SMRs and NSAIDs or Cox-2 inhibitor / SMRs and tramadol or acetaminophen) seem to be more effective than single agents. 39  Side-effects: The main common side-effect shared by SMRs is drowsiness and dizziness due to the effect on the central nervous system (CNS). Less common joint adverse events include nausea, vomiting, appetite loss and headache. 39 Specific side-effects of each drug are listed in Table 2.

Method of Grading of Evidence
An  Table 3 and at least two of the three reviewers (DJvR, AJvR, CV) deemed its content appropriate to the review. The Strength of Recommendation Taxonomy (SORT) grading system was used to grade the level of evidence of each research article. As a grading system, SORT offers a more patient-centred approach, focussing on "patient-oriented outcomes that measure changes in morbidity or mortality". 61

Results
The use of SMRs and the specific outcome of the literature review, evidence rating and clinical recommendations for general practitioners are summarised in Table 4.

Discussion
The aim of this paper was to review evidence for the possible use of SMRs in the treatment of sports injuries. The main findings are that limited original research studies are available, 117 and it appears that the current use of SMRs is mainly based on case reports and reviews that were not done systematically. Also, studies mostly make use of combination drugs rather than single agents. This complicate drawing conclusions on efficacy of SMRs specifically. 117 Regarding specific conditions, many of the studies use vague terminology and did not confirm a specific diagnosis. From our findings there are some evidence that SMRs can be effective in non-specific lower back pain (acute and chronic lower back muscle strains, ligament sprains, soft tissue contusions) 67,69-71,74-77 , as well as for whiplash associated disorder [82][83][84] , mechanical neck disorders 84 , piriformis syndrome [91][92][93] , lateral epicondylosis [97][98][99][100][101][102] , and plantar fasciitis. [103][104][105][106] An interesting finding points toward the use of SMRs (specifically BotA) in the management of recalcitrant anterior knee pain. Current evidence is promising, but only one RCT in highly selected and refractory cases of anterior knee pain that exhibit muscle imbalance (vastus medialis and vastus lateralis) has been conducted, which shows reduced pain and improved function in conjunction with exercise rehabilitation. 95 Therefore more research is required. [94][95][96] It does not appear if there is a role for SMRs as part of combination management for acute cervical strains [80][81] , post-exercise muscle soreness [87][88] , or myofascial pain syndrome [110][111][112][113][114][115][116]  Combination drugs seem to be superior compared to single agents 5. Side-effect profile is a concern a. In cases where the search results were either too broad or restricted or may have been non-satisfactory in focus the keywords 'neuromuscular blocking agent' , 'nondepolarizing agent' , 'pain' , 'anti-spasmolytic' and 'analgesic' were also employed.
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