A combination of pharmacological and non-pharmacological interventions are important, and they may be used together to manage a patient’s pain. For patients with chronic MSK pain, clinicians and patients should initially select non-pharmacologic treatment, including home exercises and multidisciplinary rehabilitation protocols. In patients with chronic MSK pain who have had an inadequate response to non-pharmacologic therapy, pharmacologic treatment with NSAIDs should be considered as first-line therapy with or without adjuvant therapy [46].
General Recommendations for Musculoskeletal Pain Management [19, 41]
-
1.
Patient’s education about their condition, self-help resources, and management options and use shared decision-making processes. This includes appropriate advice about nonpharmacological treatment strategies, such as physical activity, rest, exercise, and so on.
-
2.
Comprehensive patient assessments including detailed history taking with the assessment of physical and psychosocial factors. Physical examination including full neurological assessment, but radiological imaging is discouraged unless indicated.
-
3.
Multimodal and multidisciplinary interventions should be part of a treatment strategy for patients with chronic MSK pain.
-
4.
Facilitate early recovery or rapid resumption of work with continuous evaluation of the patient’s progress including the use of outcome measures.
-
5.
If other modalities are ineffective, consider the prescription of opioids by comprehensive assessments and screening for opioid abuse, the effectiveness of long-term opioid therapy, monitoring for adherence and side effects, and discontinue opioids because of lack of response, adverse effects, and abuse [24].
Multidisciplinary and Multimodal Approaches
A multimodal approach to pain management consists of using treatments from one or more clinical disciplines incorporated into an overall treatment plan [47, 48]. There is strong evidence that the concurrent use of multiple medications that work by different mechanisms of action and at different sites are associated with better analgesia with fewer side effects. This is the premise of multimodal analgesia [43, 44].
A multidisciplinary approach address different aspects of chronic pain conditions including biopsychosocial effects of the medical condition on the patient [47, 48]. Multidisciplinary pain services offer a variety of coherent treatment approaches that recognize that pain is a multifaceted problem requiring a multifaceted approach and continuity of care [49]. The core group for the multidisciplinary treatment service may include a pain medicine physician, a physiatrist, a neurologist, a physical and or occupational therapist, and a psychiatrist or clinical psychologist, according to local needs, resources, and available expertise [50]. In addition, to complete clinical evaluation, psychological evaluation, functional capabilities, disability scores, behavioral responses to pain, and all previous medical records are needed to avoid repeating appropriately performed studies and unsuccessful treatment approaches [51].
(I) Pharmacological
Pharmacological treatment is the mainstay for the management of pain. A wide range of analgesics have been used in the treatment of MSK pain (Table 1). In 1986, the World Health Organization (WHO) published the pain ladder system. Since then, the ladder has guided clinicians all over the world in treating pain [52]. The basic principles of achieving analgesia according to the WHO ladder focus on the main key principles that ensure the analgesic should be taken by the simplest route of administration (e.g., by the mouth), on a regular basis (e.g., by the clock), according to the type and intensity of the pain (e.g., by the ladder) and by the patient whenever possible [7, 36].
Table 1 Summary of the non-opioid analgesics An updated WHO ladder, e.g., a four-steps ladder (Fig. 2), as opposed to the 1986 “ladder”, reflects the advances in non-opioid modalities for achieving better pain relief. The integrative medicine therapies can be adopted in each step for reducing or even stopping the use of analgesics for all types of pain. If the non-opioids and weak opioids fail, minimally invasive interventions in step 3 can be recommended before upgrading to strong opioids. The revised four-step analgesic ladder aligned with integrative medicine principles and minimally invasive interventions is recommended for control of chronic non-cancer pain, including musculoskeletal pain, in order to integrate multimodality therapies for patients who are suffering from pain and can be a key factor in mitigating the opioid epidemic [53].
List of pharmacological treatments [6, 36, 37, 43, 44]
1. Simple analgesics
|
Non-steroidal analgesic and antipyretics
|
ASA
|
Acetaminophen (paracetamol)
|
Non-steroidal analgesic and anti-inflammatory (NSAIDs)
|
Non-selective COX inhibitors
|
Selective COX-2 inhibitors
|
2. Opioids
|
Weak opioids
|
Strong opioids
|
Mixed agonist-antagonists
|
3. Adjuvants
|
Anticonvulsant
|
Gabapentin
|
Pregabalin
|
Carbamazepine
|
Antidepressants
|
Tricyclic antidepressants, e.g., amitriptyline
|
SNRIs e.g., duloxetine
|
Local anesthetics
|
Lidocaine
|
Mexiletine
|
Topical agents
|
Lidocaine patch or solution
|
Diclofenac gel or patch
|
Musculoskeletal agents
|
Baclofen
|
Tizanidine
|
Cyclobenzaprine
|
Anxiolytics
|
Others
|
NMDA inhibitors, e.g., ketamine
|
α-2 Agonists e.g., clonidine
|
Calcitonin
|
Others
|
Commonly Used Analgesics for Musculoskeletal Pain
(1) Non-opioid analgesics (Table
1
)
• Acetaminophen (paracetamol)
Paracetamol is thought to act both centrally and peripherally. It reduces prostaglandin synthesis from arachidonic acid via inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2. Paracetamol should be considered alone or in combination with NSAIDs in the management of pain in patients with MSK. Generally, paracetamol has been used for pain relief across a wide range of indications because of its relative effectiveness in many pain conditions, high tolerability, and minimal adverse effects [41, 54].
Acetaminophen is conditionally recommended for patients with knee, hip, and/or hand OA. A meta-analysis has suggested that the use of acetaminophen as monotherapy may be ineffective [55]. For those with intolerance of or contraindications to the use of NSAIDs, acetaminophen may be appropriate for short-term use. Regular monitoring for hepatotoxicity is required for patients who receive acetaminophen on a regular basis and beyond the maximum dosage of 3 g daily [56].
Acetaminophen is available in a fixed-dose combination product with codeine with 30–60 mg and acetaminophen 300–1000 mg, marketed under the tradename Tylenol-3.
• NSAIDs
NSAIDs should be considered in the treatment of patients with chronic non-specific LBP and osteoarthritis (OA) [40]. Oral NSAIDs are strongly recommended for patients with knee, hip, and/or hand OA. Oral NSAIDs remain the mainstay of pharmacologic management of OA, and their use is strongly recommended. A large number of trials have established their short-term efficacy. Oral NSAIDs are the initial oral medication of choice in the treatment of OA, regardless of anatomic location, and are recommended over all other available oral medications [55, 56].
○ Non-specific NSAIDs
These have analgesic and anti-inflammatory properties and may be used as the sole method of treatment for mild-to-moderate pain. They have a “ceiling effect” to analgesia, and may lead to an increase in adverse effects [36, 57]. Clinical considerations for the safety of long-term use of NSAIDs include appropriate patient selection, regular monitoring for the development of potential adverse gastrointestinal, cardiovascular, and renal side effects, and potential drug interactions. Doses should be as low as possible, and NSAID treatment should be continued for as short a time as possible [56]. Prolonged use of NSAID treatment is also associated with other adverse effects including inhibition of platelet function and increased bleeding time, as well as bronchospasm following the administration of aspirin and other NSAIDs in some patients with asthma [36, 57].
○ COX-2 selective inhibitors (COX-2)
COX-2 selective inhibitors refer to a class of analgesic and anti-inflammatory drugs. COX-2 is found in inflammatory cells, tissue damage, synovia of joints, endothelium, and the CNS [37, 43].
COX-2 selective inhibitors are as effective as classical NSAIDs for the treatment of mild-to-moderate pain. However, COX-2 had fewer gastrointestinal side effects than traditional NSAIDs, but long-term use of COX-2 inhibitors may be associated with increased risk of cardiovascular side effects and this should be taken into account especially in cardiac and susceptible patients [40]. The most commonly used COX-2 selective inhibitor in the United States is celecoxib.
○ Topical NSAIDs
Topical NSAIDs, like topical diclofenac, are effective for reducing musculoskeletal pain and should be considered in the treatment of patients with chronic pain conditions, particularly in patients who cannot tolerate oral NSAIDs [58]. Topical NSAIDs are strongly recommended for patients with knee OA and conditionally recommended for patients with hand OA. In the United States, the FDA approved topical diclofenac in 2007 for osteoarthritic pain, responsive in the joints of the hand, knees, and feet in particular. Topical NSAIDs are preferred and should be considered prior to the use of oral NSAIDs because they are associated with the least systemic exposure. In hip OA, the depth of the joint beneath the skin surface suggests that topical NSAIDs are unlikely to confer benefit [56].
(2) Opioids:
(Table
2
)
Opioids produce their effect by acting as agonists at opioid receptors, which are found in the brain, spinal cord, and sites outside the CNS. There are three types of opioid receptors: mu (μ), delta (δ), and kappa (κ) [32, 44].
Table 2 Summary of the commonly used opioids Opioids are available in different forms and can be used by different routes of administrations, e.g., oral, sublingual, IV, IM, SC, transdermal, or neuraxial.
The main indication for opioids is to provide analgesia and pain relief for both cancer and non-cancer pain. At the same time, most opioids have a similar spectrum of adverse effects, e.g., respiratory depression, sedation, nausea/vomiting, and constipation [44, 59, 60].
It is important to know that opioids are not the first-line therapy for chronic pain; the risks, benefits, and availability of non-opioid treatments should be addressed first with patients [61]. Opioids should be considered for short- to the medium-term treatment of carefully selected patients with chronic non-malignant pain, for whom other therapies have been insufficient and the benefits may outweigh the risks of serious harms such as addiction, overdose or even death. Patients prescribed opioids should be advised of the likelihood of common side effects such as nausea and constipation [40].
The dramatic rise in the prescription of opioids, resulting from the increase in the prevalence of chronic pain, and the increase in dosage and frequency of prescriptions lead to overdose and death. The risks associated with opioid use may have created a growing need for clinical guidance on decision-making for opioid prescriptions [6].
The ongoing opioid crisis lies at the intersection of two substantial public health challenges “reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications” [62]. The influence of polysubstance abuse and the use of illicit opioids like synthetic fentanyl may also contribute heavily to overdose deaths as discussed above.
In a systematic review, three studies from the USA found that the prevalence of opioid dependence ranged from 3 to 26% in patients who were using opioids for chronic pain [63].
Another systematic review found a wide range of estimates of the rates of misuse of opioids used to treat patients with chronic pain, depending upon, among other things, study setting and case definition. It concluded that rates of misuse averaged between 8 and 12% [64].
(3) Adjuvants analgesics:
(Table
3
)
• Anticonvulsants (e.g., gabapentin, pregabalin, carbamazepine)
Table 3 Summary of the adjuvant analgesics These medications were originally developed to treat seizures, but they are used to treat some forms of pain including neuropathic pain. Gabapentin and pregabalin are effective for the treatment of patients with neuropathic pain, and FDA approved in the United States for neuropathic pain conditions like spinal cord injury, shingles, and diabetic neuropathy. These medications have a more tolerable side-effect profile compared to other anti-convulsants. There is recent concern of respiratory depression when this medication is used in conjunction with CNS depressants, including opioids, and in patients with baseline respiratory impairment. Flexible dosing may improve tolerability. Perioperative gabapentinoids are a useful component of perioperative multimodal analgesia and have been shown to reduce opioid requirements. Pregabalin is recommended also for the treatment of patients with fibromyalgia [65, 66].
Gabapentinoids bind to the α2-δ-subunit of neuronal voltage-gated calcium channels and thus reduce the influx of calcium ions in hyperexcitable neuronal states [65, 66]. Carbamazepine is approved by the FDA in the United States for the treatment of trigeminal neuralgia. It seems to have a specific effect, however potential adverse events should be discussed [40].
• Anti-depressants
Tricyclic antidepressants (TCA) (e.g., amitriptyline and nortriptyline) have an analgesic effect that is demonstrated to be independent of their antidepressant effect. The pharmacological actions of TCAs can be linked to their effect as a calcium channel antagonist, sodium channel antagonist, and their NMDA receptor antagonist effect. More specifically, the analgesic effect is believed to be due to the presynaptic reuptake inhibition of the monoamines such as serotonin and norepinephrine [38, 65, 66]. While some state that tricyclic antidepressants should not be used for the management of pain in patients with chronic low back pain [65, 66], recent studies have indicated that low doses of amitriptyline may be an effective treatment for low back pain [67]. There is also anecdotal evidence that nortriptyline may have a beneficial effect, and further research may be indicated in this area.
Serotonin norepinephrine re-uptake inhibitor (SNRI) (e.g., duloxetine 60–120 mg) should be considered for the treatment of patients with a variety of chronic pain conditions such as diabetic neuropathic pain, fibromyalgia, osteoarthritis, and LBP [61]. Selective serotonin re-uptake inhibitors (SSRIs) such as fluoxetine (20–80 mg) may be considered for the treatment of patients with fibromyalgia, although it has not been successful in treating many forms of neuropathic pain [6, 61].
• Musculoskeletal agents
Musculoskeletal agents commonly used for pain treatment include baclofen, tizanidine, and cyclobenzaprine. Baclofen is a gamma-aminobutyric acid (GABA) agonist whose method of action is not fully understood, but can inhibit monosynaptic and polysynaptic reflexes at the spinal level. It is used as a skeletal muscle relaxant as well as in the treatment of spasticity. Tizanidine is a central alpha-2 adrenergic receptor agonist with resulting inhibition of spasticity by increasing presynaptic inhibition. Cyclobenzaprine is a muscle relaxant thought to act primarily via 5-HT2 receptor antagonism on the brainstem, impacting both gamma and alpha motor neurons. Carisoprodol is metabolized to meprobamate, which is both sedating and possibly addictive, so the use of carisoprodol is not recommended, particularly because alternatives are available [68].
• Anxiolytics
Anti-anxiety medications are often prescribed to treat the anxiety that accompanies acute pain as well as anxiety resulting from fluctuations in chronic pain. They may also be prescribed for co-morbid anxiety disorders such as generalized anxiety disorder, panic disorder, post-traumatic stress disorder, and agoraphobia, which as a group have a prevalence estimated in the range of 30% in patients with chronic pain [69]. Some shorter-acting benzodiazepines carry a risk of abuse and addiction, for example lorazepam. Concurrent use of opioids and respiratory depressants like benzos have been implicated in a higher risk of adverse side effects, especially overdose-related deaths. There is poor and little evidence to support long-term benzodiazepine usage, and treatment should therefore be given for the short term until the patient can be placed on the appropriate long-term treatment, i.e., SSRIs [70].
• Alpha-2-adrenergic agonists
The analgesic activity of α2-agonists may be mediated by both supraspinal and spinal mechanisms. These drugs decrease dorsal horn neuronal firing and inhibit substance P release by affecting the α2A and α2C subgroups in the central nervous system, resulting in sedation, analgesia, and sympatholytic effects [71]. Clonidine and tizanidine have been used in the treatment of chronic pain disorders. Tizanidine has also been used in myofascial pain disorders as well as for painful muscle spasms [64]. Dexmedetomidine is eight times more specific for α2-adrenoceptors than clonidine, but has been studied for chronic pain [66, 72].
• Topical agents
Topical lidocaine patches (5%) may be used for localized nociceptive pain, neuropathic pain, and post-herpetic neuralgia. These are worn 12 h on and 12 h off. Few side effects such as skin redness and irritation may be reported [73].
Topical capsaicin patches (8%)
Evidence supports that capsaicin can be used for the treatment of both chronic neuropathic and musculoskeletal pain. The main adverse reaction with topical capsaicin patches is localized skin irritation. Due to its poor efficacy, it should be considered in the treatment of patients when first-line pharmacological therapies have been ineffective or not tolerated [74]. Topical capsaicin is FDA approved for the treatment of peripheral diabetic neuropathy of the feet, and postherpetic neuralgia (PHN) in the United States [75].
• Bone marrow concentrate (BMC)
The use of bone marrow concentrate for the treatment of musculoskeletal disorders has become increasingly popular over the last several years. Typically, bone marrow is obtained by iliac crest aspiration, and contains progenitor cells like mesenchymal stem cells, as well as cytokine and growth factors [76]. Studies have suggested good-to-great pain relief with BMC use, and injection is a safe procedure when performed by trained physicians with the appropriate precautions under image guidance utilizing a sterile technique.
The position statement for the use of homologous BMC in MSK pain developed by Manchikati et al. recommends a method of preparation with minimal manipulation and suggests moderate and emerging evidence of beneficial utility in various musculoskeletal and spinal conditions [77]. Evidence for use of BMC is highest in osteoarthritis of the knee (level II), moderate for knee cartilage conditions or for disc injections for degenerative disc disease (level III), and limited evidence for all other conditions when performed by trained physicians under image guidance with sterile technique and precautions [77].
(II) Non-pharmacological
(1) Physical modalities
These modalities may be valuable and successful in the management of both acute and chronic pain. Muscle spasm is usually the main cause of pain; heat and cold application reduces spasmodic muscle shortening, which in turn may be caused by direct muscular trauma or underlying primary neurologic or skeletal disease. Passive treatment programs such as hot packs, massage, and ultrasound may be appropriate for a short period of time; however, a home exercise program, stretching, and self-applied modalities should be implemented early [82,83,84]. There are no large landmark clinical trials of these modalities so evidence must be considered as limited.
• Cryotherapy
Therapeutic cold is applied directly to an injured area to reduce hemorrhage and vasodilation, decreases the local inflammatory response, edema production, and pain perception [85]. The PRICE (protection, rest, ice, compression, and elevation) method is commonly prescribed for acute sports-related injuries as well as chronic painful conditions [86].
Cryotherapy is not recommended in patients with peripheral vascular disease (e.g., Raynaud’s disease). Also, prolonged exposure to cold should be avoided on superficial nerves such as ulnar and peroneal nerves at the medial elbow and head of the fibula [85, 86].
• Heat therapy
Heat application, in both subacute and chronic pain conditions, produces increased collagen extensibility, increased blood flow, metabolic rate, and inflammation resolution. Decreased joint stiffness, muscle spasm, and pain are also positive effects of heat therapy. Heat raises the pain threshold and acts directly on the muscle spindle, decreasing spindle excitability [87]. Therapeutic heat application is used in combination with prolonged stretch to reduce musculoskeletal contractures, joint stiffness, and chronic inflammatory diseases, thus leading to decreased pain and increasing range of motion and function [88, 89].
Superficial heat therapy is contraindicated in cases with sensory impairment, vascular insufficiency, malignancy and infection, while deep heat is contraindicated in pregnancy, sensory deficit, and metal implants [50].
• Transcutaneous electrical nerve stimulation therapy (TENS)
“TENS” is based on the gate control theory of pain from Melzack and Wall, where the preferential activation of large Aβ-fibers inhibits the transmission of painful impulses [90]. It has been used to manage acute and chronic pain, e.g., postoperative pain, complex regional pain syndrome, phantom limb pain, and peripheral nerve injury [91,92,93]. It is contraindicated in patients with a cardiac pacemaker [93]. TENS has been used anecdotally for use in low back pain, but studies show conflicting recommendations on the matter. TENS has been shown to be effective in osteoarthritic and neuropathic pain [94].
• Acupuncture
Acupuncture is an ancient Chinese therapy practiced for more than 2500 years to cure disease and relieve pain. It depends on the use of thin metal needles that are inserted into specific body sites and stimulated manually or electrically. Acupuncture is considered an invasive procedure and needs a professional physician or practitioner to perform it. There is no evidence that acupuncture is more effective than other treatments such as NSAIDs for low back pain or neck pain [95, 96]. Side effects are localized hyperemia, syncopal attacks, and hematoma [97].
• Therapeutic exercise
Acute injuries of the musculoskeletal system may lead to contraction and shortening of the muscles as a protective mechanism. So, treatment usually consists of immobilization, compression, and cryotherapy. When pain decreases, mobilization should be regained gradually, but if muscle became chronically shortened and contracted, additional pain will result. The best treatment in such cases is combined gradual stretching and strengthening exercises. Patient education is mandatory about a therapeutic exercise regimen at home once therapeutic sessions have ceased [98, 99].
Therapeutic exercise consists of passive movements, active-assistive exercises, active exercises, stretching, and relaxation exercises. These may be used in combination with other physical modalities [100, 101].
(2) Psychological
There is growing evidence that a range of psychological factors can contribute to the experience and impact of pain, as well as the development of persisting pain. These factors should be considered and targeted by specific treatments, e.g., cognitive behavioral therapy, explanation, reassurance, stress reduction, and counseling [102, 103].
(3) Pain interventions
Pain interventions are minimally invasive procedures that relieve acute and chronic pain and minimize the use of analgesics when appropriately indicated. Neural blockade can be used for diagnostic, prognostic, or therapeutic purposes. Image guidance tools such as ultrasound, C-arm, CT, or MRI can be used during the intervention when clinically indicated. Most of the interventions are conducted on an outpatient or day-care basis [32, 104, 105].
Therapeutic options include:
-
Medications, e.g., local anesthetics, steroids, opioids, Botulinum toxin, α-2 adrenergic agonists.
-
Destructive: neurolytics (alcohol or phenol)
-
Physical: Radiofrequency (pulsed or thermal RF) and cryo-analgesia
Intervention trials should focus on outcomes based on six core domains defined by the IMMPACT (Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials) to be: pain, physical functioning, emotional functioning, participant rating of improvement and satisfaction with treatment, symptoms and adverse events, and participant disposition [106].
A list of the common pain interventions that can be used for the management of MSK pain is shown in Table 4. Additionally, in other chronic pain conditions, there is often overlapping musculoskeletal pain. Therefore, the co-existence of underlying neuropathic or other pain syndromes often requires the use of these interventions.
Table 4 List of the interventions for chronic pain management (4) Surgical interventions [19, 32]