Contents part 1: Introduction

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Researchers have found evidence that psychosocial variables are strongly linked to the transition from acute to chronic pain disability and that psychosocial variables generally have more impact than biomedical or biomechanical factors on back pain disability. (Linton, 2000) Thus, when clinical progress is insufficient or protracted, the clinician should consider the possibility of delayed recovery and be prepared to address any confounding psychosocial variables.

Medical vs. Self-Management Model
Understandably, patients want their chronic pain “cured” or eliminated. Unfortunately, no definitive cures currently exist for the majority of persistent pain problems, such as axial spine pain, peripheral neuropathies, and fibromyalgia. As is the case with all chronic medical conditions, chronic pain must be managed, when it cannot be cured. In the medical model, responsibility resides primarily with the physician. However, emphasis is increasingly being placed on encouraging patients to accept some pain and to make self-management efforts that can improve function and quality of life, even if they don’t eliminate all pain. An approach that emphasizes participation in daily activities despite pain as well as fostering a willingness to have pain present without responding to it may aid in reducing the “distressing and disabling influences of pain.” (McCracken, 2005) The self-management approach places primary responsibility on the person with chronic pain. Self-management strategies can significantly improve a patient’s function and quality of life, while reducing subjective experiences of pain. It is important to educate patients to avoid persistent and unrealistic expectations for an elusive cure when none exists. This unrealistic curative view, often unwittingly fostered by healthcare providers, predictably leads to repeated failures, delayed recovery, and unnecessary disability and costs.
Self-efficacy is a psychological construct related to that of control. Believing that one can perform a task or respond effectively to a situation predicts pain tolerance and improvements in physical and psychological functioning. Research suggests that “a primary aim of chronic low back pain rehabilitation should be to bring about changes in catastrophic thinking and self-efficacy,” because greater self-efficacy improves pain, functional status, and psychological adjustment. (Keefe, 2004) Researchers posit several explanations for why self-efficacy works to control pain, including the theory that people who expect success are less likely to be stymied when confronting the challenge of pain.
The goals of self-management and self-efficacy reinforce the benefits that accrue when people take a more active role in managing their pain. While self-efficacy as a sole method may not be sufficient to achieve pain control in many situations, treatment should include efforts to help patients actively manage pain.
Risk Stratification
Importance of early identification
Patients not responding to initial or subacute management (see Clinical Topics Section MTUS) or those thought to be at risk for delayed recovery should be identified as early as possible. Simple screening questionnaires may be used early in the clinical course to identify those at risk for delayed recovery. Those at risk should be more aggressively managed to avoid ineffective treatment and needless disability. Factors that help identify at-risk patients include: (1) those unresponsive to conservative therapies demonstrated to be effective for specific diagnoses in others; (2) the presence of significant psychosocial factors negatively impacting recovery; (3) loss of employment or prolonged absence from work (which has a high predictive value); (4) previous history of delayed recovery or incomplete rehabilitation; (5) lack of employer support to accommodate patient needs; and (6) a history of childhood abuse (verbal, physical, sexual, etc.) abandonment, or neglect (adverse childhood experience, also known as ACE).
Subacute Delayed Recovery
Complaints of pain are the most common obstacles to return to work. Undertreatment of pain and/or unrealistic expectations may play a role in delayed recovery. However, the subacute phase is a critical time for the injured worker, as additional time away from work may result in adverse medical (e.g., overtreatment), familial, economic, and psychological consequences (e.g., depression and anxiety), which can exacerbate pain complaints. When the physician recognizes that the problem is persisting beyond the anticipated time of tissue healing, the working diagnosis and treatment plan should be reconsidered, and psychosocial risk factors should be identified and addressed. If necessary, patients should be directed to resources capable of addressing psychosocial barriers to recovery.
Increasingly, time-limited Cognitive Behavioral Therapy (CBT) is being used successfully to do just that.

Literature review meta-analysis has shown the CBT model of intervention to be more effective than wait list controls and alternative active treatment. (Morely, 1999) Both the cognitive and behavioral intervention components of CBT have been found effective.

The behavioral component of CBT focuses on physiologic self-management techniques such as reinforcement for participation in functional activities, progressive relaxation, and autogenic/self-hypnosis. These techniques decrease the stress arousal response system associated with chronic pain. CBT techniques may be especially effective for patients with high stress arousal response, guarding behavior and history of ACE.
Patients with Intractable Pain

Studies have shown that the longer a patient remains out of work the less likely he or she is to return. Similarly, the longer a patient suffers from chronic pain the less likely treatment, including functional restoration efforts, will be effective. Nevertheless, if a patient is highly motivated and prepared to make the effort, a multidisciplinary evaluation for admission for treatment in a functional restoration program, (consistent with California Health and Safety Code section 124960) should be considered.

Assessment Approaches
History and Physical Examination
The treating physician has limited sources of objective information. Therefore, it is important for the physician to take a thorough history in clinical assessment and treatment planning for the patient with chronic pain. Whenever possible, this history should include a review of medical records. Clinical recovery may be dependent upon identifying and addressing previously unknown or undocumented medical and/or psychosocial conditions. A thorough physical examination is also important to establish or confirm diagnoses and to observe and better understand pain behaviors. The history and physical examination also serves to establish reassurance and patient confidence. Diagnostic studies should be ordered in this context and not simply for screening purposes.
If a diagnostic workup is indicated and it does not reveal any clinically significant contraindications, the physician should encourage the patient to engage in an active rehabilitation and self management program. Effective treatment of the chronic pain patient requires familiarity with patient-specific past diagnoses, treatment outcomes, persistent complaints and psychosocial variables.
Evaluation of Psychosocial Factors
Psychosocial factors have proven better predictors of chronicity than clinical findings. Such variables/factors can and should be assessed; they include a history of abuse, anxiety, depression, fear-based avoidance of activity, catastrophizing, self-medication with alcohol or other drugs, patient/family expectations, medical-legal claims management issues, and employer/supervisor/worksite factors.
Childhood trauma may contribute significantly to pain chronicity. A 2010 CDC Study of 26,000 Americans adults revealed that 60% reported childhood familial problems, 15% experienced physical abuse, more than 12% had been sexually abused, and nearly 9% had at least five "adverse childhood experiences” (ACE). (CDC, 2010) Such events (per the ongoing ACE study) correlate with delayed recovery and poor outcomes from injury. Clearly, assessment of psychosocial factors is a critical element of patient evaluation.
Functional Restoration Approach to Chronic Pain Management
Many injured workers require little treatment, and their pain will be self-limited. Others will have persistent pain that can be managed with straightforward interventions and do not require multi-disciplinary treatment. However, for patients with more refractory problems and sufficient motivation, a multidisciplinary, functionally oriented (not pain-oriented) treatment approach with a goal of independent self-management may be a more effective treatment approach.
Functional restoration is an established treatment approach that aims to minimize the residual complaints and disability resulting from acute and chronic medical conditions. Functional restoration may be considered if there is a delay in return to work or a prolonged period of inactivity. Functional restoration is the process by which the individual acquires the skills, knowledge, and behavioral changes necessary to avoid preventable complications and assume or re-assume primary responsibility (“locus of control”) for his or her physical and emotional well-being post injury. The focus is on increasing activities of daily living (ADL), including returning to work. The individual thereby maximizes functional independence and the pursuit of vocational and avocational goals, as measured by functional improvement (see 8 CCR § 9792.20 (f)).
Independent self-management is the long-term goal of all forms of functional restoration. The process and principles of functional restoration can apply to a wide range of conditions, including acute injuries (e.g., sports, occupational), catastrophic injuries (e.g., brain and spinal cord injury), and chronic conditions (e.g., chronic pain and multiple sclerosis).
It should be emphasized that functional restoration is not necessarily a full-time, multi-week treatment program, but rather an approach that emphasizes patient empowerment and personal responsibility.
A coordinated, goal-oriented, functional restoration approach can incorporate pharmacologic treatment, therapeutic interventions, CBT, and physical rehabilitation.
Using medications in the treatment of pain requires a thorough understanding of the mechanism underlying the pain as well as the identification of comorbidities that might predict an adverse outcome (see the DWC “Guideline for the Use of Opioids to Treat Work-Related Injuries”). Choice of pharmacotherapy must be based on the type of pain to be treated, though more than one pain mechanism may be involved. The physician should tailor medications and dosages to the individual, taking into consideration patient-specific variables such as comorbidities, other medications, and allergies. The physician should be knowledgeable regarding prescribing information and adjust the dosing to the individual patient. If the physician prescribes a medication for an indication not in the approved FDA labeling, he or she has the responsibility to be well informed about the medication and confident that its use is scientific and evidence based. When effective, medications should provide a degree of analgesia that allows the patients to engage in rehabilitation, improvement of basic activities of daily living, and/or possibly return to work. No drugs have been proven to reverse, cure, or “heal” chronic pain. In addition, periodic review of the ongoing chronic pain treatment plan for the injured worker is essential.
When choosing an invasive procedure to treat a specific chronic pain problem, the provider must make a complex judgment in order to ensure that the desired and expected outcome is worth the risk involved.
Please refer to Part 2 of the Chronic Pain Treatment Guidelines to find specific guidelines on chronic pain treatments that include pharmacotherapy, invasive pain procedures, psychological and behavioral therapies, physical and occupational therapies, and other approaches. The treatment must be tailored to the individual case. Regardless of who is providing the treatment, be it an individual provider, a multidisciplinary group of providers, integrated interdisciplinary pain program, or a functional restoration program, it is important to design a treatment plan that explains the purpose of each component of the treatment. Furthermore, demonstration of functional improvement is necessary at various milestones in the functional restoration program to justify continued treatment.

Pain Outcomes and Endpoints
Because pain is a subjective experience, it cannot be readily validated or objectively measured. (AMA, 2001) (Therefore, unlike many other chronic diseases, which may have objective measurements that can be used to assess the extent of the problem and treatment outcomes, chronic pain has no objective measurement. Measuring a patient’s pain requires correlating objective data with the patient’s subjective reporting to arrive at a comprehensive outcome representing the state of pain.
Complicating the measurement of pain is that there is often a wide variability in how much pain a given stimulus or injury will cause. This variability is influenced by genetics, mood, beliefs, sex, ethnicity, and other factors such as early-life pain experiences with pain. (Kim, 2004)
Chronic pain is often associated with an overall reduction in the patient’s quality of life which may lead to depression, anxiety, impaired social and physical function, and sleep disturbance. Moreover, there appears to be relative independence between pain and these co-existing stressors. Therefore, to capture the pain experience, it is necessary to also define and characterize these related domains. (Malhotra, 2012) In addition, it is essential to understand the extent to which pain impedes function. (AMA, 2001)

The physician treating patients in the workers’ compensation system must be aware that just because an injured worker has reached a permanent and stationary status or maximal medical improvement does not mean that the patient is no longer entitled to future medical care. The physician should periodically review the patient’s course of treatment and any new information about the etiology of the pain or the patient's state of health. Continuation or modification of pain management depends on the physician’s evaluation of the patient’s progress toward treatment objectives. If it is unsatisfactory, the physician should assess how appropriate it is to continue the current treatment plan and whether to consider other therapeutic modalities. If the patient taking controlled substances to treat chronic pain experiences decreased pain and can demonstrate increased level of function or improved quality of life, then the treatment has had a satisfactory outcome.

Additionally, fluctuations are likely to occur in the natural history of patients with chronic pain. If exacerbations and “breakthrough” pain occur during the chronic clinical course, adjustments to the treatment will be necessary.
Chronic pain affects approximately 100 million dults in the U.S., with a national economic cost exceeding half a trillion dollars per year. Pain is a uniquely individual and subjective experience. Further, while pain can be a symptom of another condition, when it becomes persistent, it can become a disease in its own right, one that is associated with structural and functional changes of the peripheral and central nervous system. These changes can lead to the generation and maintenance of chronic pain conditions, with associated disability. While biologic mechanisms play a role in the perception of pain, it is important to recognize that psychological and environmental factors play an important role as well. Recognition of these factors will allow the physician to better (1) treat the recently injured patient, (2) identify the “at risk” patient, and (3) refer the patient with intractable chronic pain to the appropriate resources. A full assessment of the patient is required to determine the best approach in each case.
Therapy for chronic pain ranges from single modality approaches for the straightforward case to comprehensive interdisciplinary functional restoration care for the more challenging case. Therapeutic components such as pharmacologic, interventional, psychological, and physical approaches have been found to be most effective when performed in an integrated manner. All therapies should aim to restore function rather than merely eliminate pain, and demonstrated functional improvement is essential in assessing treatment efficacy. Typically, with increased function comes a perceived reduction in pain and increased perception of its control. These changes ultimately lead to an improvement in the patient’s quality of life.

ACOEM Occupational Medicine Practice Guidelines-part of Reed Group® DisabilityGuidelines™. Copyright 2008-2014 Reed Group, Ltd., All rights reserved.

American Medical Association (AMA). Guides to the Evaluation of Permanent Impairment. Fifth Edition. 2001:566, 578.

Barad MJ, Ueno T, Younger J, Chatterjee N, Mackey S. Complex regional pain syndrome is associated with structural abnormalities in pain-related regions of the human brain. J Pain. 2014;15:197-203.

Costigan MJ, Scholz, Woolf CJ. Neuropathic pain: A maladaptive response of the nervous system to damage.Annu Rev of Neuroscienc. 2009;32:1-32.

CDC (Centers for Disease Control and Prevention). Adverse Childhood Experiences Reported by Adults--- Five States, 2009. Morbidity and Mortality Weekly Report (MMWR). 2010 Dec 17; 59(49):1609-1613.
Engel GL. The need for a new medical model: a challenge for biomedicine. Science. 1997;196: 129–36
Feinberg SD, Gatchel R, Stanos S, Feinberg R, Johnston-Montieth V. Interdisciplinary functional restoration and pain programs, in Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Behavioral Approaches: The AMERICAN ACADEMY OF PAIN MEDICINE Textbook on Patient Management. March 2013:Springer Science+Business Media.

Flor H, Fydrich T. et al. Efficacy of multidisciplinary pain treatment centers: A meta-analytic flow. Pain. 1992;49(2): 221-230.

Gatchel RJ, Bruga D. Multidisciplinary intervention for injured workers with chronic low back pain. SpineLine. 2005;(Sept/Oct): 8-13.
Gatchel RJ, Peng YB, Peters ML, Fuchs PN, Turk DC. The biopsychosocial approach to chronic pain: Scientific advances and future directions. Psychological Bulletin. 2007;133(4):581-624.
Guzman J, Esmail R, et al. Multidisciplinary rehabilitation for chronic low back pain: systematic review. British Medical Journal. 2001;322(7301): 1511-6.
Hanson R, Gerber K. Table 2.1: Contrasting pain models Coping with Chronic Pain: A Guide to Patient Self-Management. New York, NY, Guilford Press. 1993:30.
Hughes, J. ed. Pain Management: From Basics to Clinical Practice. Churchill Livingstone, Edinburgh, UK. 2008.
IOM (Institute of Medicine). Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press. 2011.
Keefe FJ, Rumble ME, Scipio CD, Giordano LA, Perri LM. 2004. Psychological aspects of persistent pain: Current state of the science.J Pain. 2004. 2004;5(4):195-211.
Kim H, Neubert JK, San Miguel A, Xu K, Krishnaraju RK, Iadarola MJ, Goldman D, Dionne RA.

Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain. 2004;109:488-96.

Kindler LL, Bennett RM, Jones KD. Central sensitivity syndromes: Mounting pathophysiologic evidence to link fibromyalgia with other common chronic pain disorders. Pain Manag Nurs. 2011;12(1):15-24.
Linton S. A review of psychological risk factors in back and neck pain. Spine. 2000;25 (9): 1148-56.
Loeser JD. Bonica's Management of Pain. Lippincott Williams & Wilkins, Philadelphia, 2001.
Mackey SC, Maeda F. Functional imaging and the neural systems of chronic pain. Neurosurg Clin N Am. 2004;15(3): 269-88.
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McCracken LM. Contextual Cognitive-Behavioral Therapy for Chronic Pain. Seattle, WA: International Association for the Study of Pain. 2005.
Medical Board of California, Guidelines for Prescribing Controlled Substances for Pain. November 2014.
Melzack R, Wall PD. The challenge of pain. New York: Penguin Press. 1996.
Merskey H, Bogduk N. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. Seattle, WA, IASP Press. 1994.
Morley S, Eccleston C, Williams A. Systematic review and meta-analysis of randomized controlled trials of cognitive behavior therapy and behavior therapy for chronic pain in adults, except headache. Pain. 1999;80: 1-13.

Turk D, Okifuji A. Chapter 2: Pain Terms and Taxonomies of Pain, in Loeser JD. Bonica’s Management of Pain. Third edition. Philadelphia, PA, Lippincott Williams and Wilkins. 2001.

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PART 2: Procedure Summary-Pain

Procedure Summary – Pain


Summary of medical evidence

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Acetaminophen (APAP)

Recommended for treatment of acute pain, chronic pain & acute exacerbations of chronic pain. With new information questioning the use of NSAIDs, acetaminophen should be recommended on a case-by-case basis. The side effect profile of NSAIDs may have been minimized in systematic reviews due to the short duration of trials. On the other hand, it now appears that acetaminophen may produce hypertension, a risk similar to that found for NSAIDs.

Acute pain: Recommended as an initial choice for treatment of acute pain. See Medications for acute pain (analgesics).

Osteoarthritis: Recommended as an initial treatment for mild to moderate pain, in particular, for those with gastrointestinal, cardiovascular and renovascular risk factors. (Laine, 2008) If pain is inadequately treated or there is evidence of inflammation, alternate pharmacologic treatment should be considered. In patients with moderate to severe disease, initial treatment with an NSAID may be warranted. The decision to use either class of drugs should be made on a case-by-case basis, incorporating factors including side effect profile and patient preferences. Current guidelines note that evidence is limited to make an initial recommendation with acetaminophen, and that NSAIDs may be more efficacious for treatment. In terms of treatment of the hand it should be noted that there are no placebo trials of efficacy and recommendations have been extrapolated from other joints. (Zhang, 2007) The selection of acetaminophen as a first-line treatment appears to be made primarily based on side effect profile in osteoarthritis guidelines. (Zhang, 2008) The most recent Cochrane review on this subject suggests that non-steroidal anti-inflammatory drugs (NSAIDs) are more efficacious for osteoarthritis than acetaminophen in terms of pain reduction, global assessments and improvement of functional status. No significant difference was found between overall safety, although patients taking NSAIDs were more likely to experience an adverse GI event. It is important to note that the median trial duration was only 6 weeks. (Towheed, 2006) See NSAIDs; NSAIDs, GI symptoms & cardiovascular risk; & NSAIDs, hypertension and renal function. Also see specific body-part chapters in the DWC MTUS.

Adverse effects: Hepatotoxicity: Acetaminophen overdose is a well-known cause of acute liver failure. Hepatotoxicity from therapeutic doses is unusual. (Hunt, 2007) A warning is given on all acetaminophen products that patients that consume ≥ 3 alcoholic drinks a day should discuss use with their physician, although a systematic review of acetaminophen use in alcoholic subjects concluded that there was little credible evidence to implicate therapeutic doses as a cause of fulminant hepatotoxicity in alcoholics. (Dart, 2007) Recent RCTs found that short-term treatment (3-5 days) of acetaminophen in newly abstinent alcoholic patients did not cause hepatic injury. (Kuffner, 2007) (Bartels, 2008) Acetaminophen, when used at recommended maximum doses, may induce ALT elevations >3× ULN in up to nearly 40% of subjects. Renal toxicity: Renal insufficiency occurs in 1 to 2% of patients with overdose. (Mazer, 2008) Hypertension and cardiovascular risk: Cohort analysis reveals that acetaminophen use is associated with hypertension but evidence from randomized controlled trials is limited. This risk is similar to that found for NSAIDs. (Forman, 2007) (Montgomery, 2008) An increased cardiovascular risk was found in the Nurse’s Health Study. (Chan, 2006) (Laine, 2007) (Laine, 2008)

Dose: Acetaminophen has been shown definitively to work synergistically with opioids, enhancing pain relief in a way that is opioid-sparing. (FDA, 2008) Despite acetaminophen's synergistic effect with opioids, fixed combination products are problematic because it is not possible to titrate the opioid dose relative to the acetaminophen dose when the fixed combination is used. Furthermore, in order for acetaminophen to produce an effective analgesic effect, it needs to be used on a regular basis. Consequently, it is best to administer acetaminophen as a single drug and on a routine basis and then, if necessary, to add an opioid as a single entity that may be titrated to effect. (Ray, 2013)

Dose: The recommended dose for mild to moderate pain is 650 to 1000 mg orally every 6 hours with a FDA-approved maximum of 4 g/day. In calculating the maximum daily dose, it is necessary to combine all sources of acetaminophen in, including many OTC preparations as well as many common opioid combinations that include acetaminophen. An FDA advisory committee has recommended new restrictions on acetaminophen, voting that the single adult acetaminophen dose should be no more than 650 mg with a maximum total dose for 24 hours, decreased to no more than 3,250 mg. (FDA, 2009) The FDA asked drug manufacturers to limit the strength of acetaminophen in prescription drug products, predominantly combinations of acetaminophen and opioids, to 325 mg per pill, to reduce the risk of severe liver injury and allergic reactions. A Boxed Warning has been added to the label of all prescription drug products that contain acetaminophen. (FDA, 2011) To help encourage appropriate acetaminophen use, the newly implemented dosing instructions of Extra Strength Tylenol® (acetaminophen) have lowered the maximum daily dose from 8 pills per day (4,000 mg) to 6 pills per day (3,000 mg). The dosing interval has changed from 2 pills every 4–6 hours to 2 pills every 6 hours. (McNeil, 2014) Acetaminophen is best administered independently and on a routine basis with, if necessary, an opioid added as a single entity that may be titrated to effect.

Actiq® (oral transmucosal fentanyl lollipop)

Not recommended for chronic non-cancer pain. ActiqÒ (oral transmucosal fentanyl citrate), a fast-acting highly potent "lollipop" painkiller produced by Cephalon, is indicated only for the management of breakthrough cancer pain in patients with malignancies who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Actiq is contraindicated in acute pain; is not for use in chronic pain; and has a Black Box warning for abuse potential.


See DWC MTUS Acupuncture Medical Treatment Guidelines for recommendations. .

Shoulder: Recommended as an option for rotator cuff tendinitis.

Carpal tunnel syndrome: Not recommended.

ODG Acupuncture Guidelines:

Initial trial of 3-4 visits over 2 weeks

With evidence of reduced pain, medication use and objective functional improvement, total of up to 8-12 visits over 4-6 weeks (Note: The evidence is inconclusive for repeating this procedure beyond an initial short course of therapy.)

A-delta fiber electrodiagnostic testing

Not recommended. See Quantitative sensory threshold (QST) testing.

Alendronate (Fosamax®)

See Bisphosphonates. Bisphosphonates are a class of drugs that inhibit osteoclast action and the resorption of bone. Alendronate (Fosamax®) is in this class.

Alexander technique

See Education.

Alprazolam (Xanax®)

Not recommended for long-term use. See Benzodiazepines. Alprazolam, also known under the trade name Xanax and available generically, is a short-acting drug of the benzodiazepine class used to treat moderate to severe anxiety disorders, panic attacks, and as an adjunctive treatment for anxiety associated with major depression.

Ambien® (zolpidem tartrate)

Ambien® is a brand name for zolpidem tartrate produced by Sanofi-Aventis. See Zolpidem (Ambien®).


Recommended. Amitriptyline is a tricyclic antidepressant. Tricyclics are generally considered a first-line agent unless they are ineffective, poorly tolerated, or contraindicated. See Antidepressants for chronic pain for general guidelines, as well as specific Tricyclics listing for more information and references.

Antianxiety drugs

See Anxiety medications in chronic pain.


See Anti-epilepsy drugs (AEDs).

Antidepressants for chronic pain

Recommended as a first-line option for neuropathic pain, and as a possibility for non-neuropathic pain. (Feuerstein, 1997) (Perrot, 2006) Tricyclics are generally considered a first-line agent unless they are ineffective, poorly tolerated, or contraindicated. Analgesia generally occurs within a few days to a week, whereas antidepressant effect takes longer to occur. (Saarto-Cochrane, 2005) Assessment of treatment efficacy should include not only pain outcomes, but also an evaluation of function, changes in use of other analgesic medication, sleep quality and duration, and psychological assessment. Side effects, including excessive sedation (especially that which would affect work performance) should be assessed. (Additional side effects are listed below for each specific drug.) It is recommended that these outcome measurements should be initiated at one week of treatment with a recommended trial of at least 4 weeks. The optimal duration of treatment is not known because most double-blind trials have been of short duration (6-12 weeks). It has been suggested that if pain is in remission for 3-6 months, a gradual tapering of anti-depressants may be undertaken. (Perrot, 2006) (Schnitzer, 2004) (Lin-JAMA, 2003) (Salerno, 2002) (Moulin, 2001) (Fishbain, 2000) (Taylor, 2004) (Gijsman, 2004) (Jick-JAMA, 2004) (Barbui, 2004) (Asnis, 2004) (Stein, 2003) (Pollack, 2003) (Ticknor, 2004) (Staiger, 2003) Long-term effectiveness of anti-depressants has not been established. (Wong, 2007) The effect of this class of medication in combination with other classes of drugs has not been well researched. (Finnerup, 2005) The “number needed to treat” (NNT) methodology has been used to calculate efficacy of the different classes of antidepressants. (Sindrup, 2005) See DWC MTUS relevant chapters.

Specifically studied underlying pain etiologies: (also see below for specific drugs)

Neuropathic pain: Tricyclic antidepressants are recommended as a first-line option, especially if pain is accompanied by insomnia, anxiety, or depression. (Saarto-Cochrane, 2007) (ICSI, 2007). Other recent reviews recommend both tricyclic antidepressants and SNRIs (i.e., duloxetine and venlafaxine) as first-line options. (Dworkin, 2007) (Finnerup, 2007).

Non-neuropathic pain: Recommended as an option in depressed patients, but effectiveness is limited. Non-neuropathic pain is generally treated with analgesics and anti-inflammatories. In guidelines for painful rheumatic conditions recommended by Perrot, it was suggested that antidepressants may be prescribed as analgesics in non-depressed patients, with the first-line choice being tricyclics initiated at a low dose, increasing to a maximally tolerated dose. (Perrot, 2006)

Specific studied disease states

Fibromyalgia: There have been 25 controlled trials that have studied the use of antidepressants for fibromyalgia, including 3 meta-analyses. Good results were found with duloxetine in treating fibromyalgia (Arnold, 2007). Several studies evaluated tricyclics. (Perrot, 2006) (Moulin, 2001) A review of two double blind, placebo controlled trials concluded that duloxetine was safe and effective in women with fibromyalgia for up to 12 weeks (with long-term studies needed). (Arnold, 2007) Duloxetine is approved by the FDA for treatment of fibromyalgia. (FDA 2010) Another review indicated that there is strong evidence that amitriptyline is effective for fibromyalgia and suggested that more information is needed regarding the role of SNRIs and SSRIs. (Goldenberg, 2007) Compared with placebo, the SNRIs duloxetine (Cymbalta) and milnacipran (Savella) are slightly more likely to reduce pain in patients with fibromyalgia, according to a new Cochrane meta-analysis, but they are not superior in terms of reducing fatigue and sleep problems or in improving quality of life, and they appear to cause more adverse effects. (Häuser, 2013)

See also the DWC MTUS chapter on Low Back Complaints.

Osteoarthritis: No studies have specifically studied the use of antidepressants to treat pain from osteoarthritis. (Perrot, 2006) In depressed patients with osteoarthritis, improving depression symptoms was found to decrease pain and improve functional status. (Lin-JAMA, 2003)

Antidepressant discontinuation: Nearly all classes of antidepressants have been linked to discontinuation reactions that are distinct from recurrence or relapse of underlying psychiatric pathology. It does appear that discontinuation reactions can occur regardless of the particular indication for use. The most common research involves discontinuation of serotonin-reuptake inhibitors (Sertonin-discontinuation syndrome).

Symptoms: Symptoms of discontinuation vary between classes of antidepressants, and between different drugs in the classes. These may include changes in mental/psychological status (confusion, restlessness, agitation, anxiety, worsening of mood, panic attacks, dysphoria, manic symptoms, and decreased level of consciousness), neurological changes (tremor, rigidity, clonus, myoclonus, hyperreflexia, ataxia, and rigidity), autonomic changes (diaphoresis, shivering, mydriasis, nausea and diarrhea), and changes in vital signs (tachycardia, hypertension, hyperthermia, and tachypnea). Commonly patients describe both psychological and somatic symptoms (the latter described as flu-like, with or without gastrointestinal physical symptoms). Symptoms are thought to occur in at least 20% to 25% of patients upon discontinuing of serotonin-reuptake inhibitors (with reports of at least 50% with drugs with shorter-half lives such as paroxetine or venlafaxine). Symptoms tend to emerge within 2 to 5 days with a usual duration of 1 to 2 weeks. The primary risk factors for this reaction include use of antidepressants with shorter half-lives, longer duration of treatment, and abrupt discontinuation.

Differentiation from depression relapse or recurrence: Differentiating factors include looking for symptoms that are more likely to occur with discontinuation reaction (dizziness, electric shock-like sensations, “rushing” sensations, headache and nausea) as well as observing for rapid reversal of symptoms (complete resolution within 1 to 2 weeks of the taper/discontinuation is less likely to be due to depression). Later onset of symptoms (after at least two to three weeks of discontinuation/tapering) or prolonged symptoms (3 weeks or greater) are more commonly associated with a relapse of psychiatric pathology or another intercurrent disease.


Tricyclic antidepressants are recommended over selective serotonin reuptake inhibitors (SSRIs), unless adverse reactions are a problem. Caution is required because tricyclics have a low threshold for toxicity, and tricyclic antidepressant overdose is a significant cause of fatal drug poisoning due to their cardiovascular and neurological effects. Tricyclic antidepressants have been shown in both a meta-analysis (McQuay, 1996) and a systematic review (Collins, 2000) to be effective, and are considered a first-line treatment for neuropathic pain. (Namaka, 2004) (Dworkin, 2003) (Gilron, 2006) (Wolfe, 2004) (Dworkin, 2007) (Saarto-Cochrane, 2007) This class of medications works in both patients with normal mood and patients with depressed mood when used in treatment for neuropathic pain. (Sindrup, 2005) Indications in controlled trials have shown effectiveness in treating central post-stroke pain, post-herpetic neuralgia (Argoff, 2004), painful diabetic and non-diabetic polyneuropathy, and post-mastectomy pain. Negative results were found for spinal cord pain and phantom-limb pain, but this may have been due to study design. (Finnerup, 2005) Tricyclics have not demonstrated significance in randomized-control trials in treating HIV neuropathy, spinal cord injury, cisplatinum neuropathy, neuropathic cancer pain, phantom limb pain or chronic lumbar root pain. (Dworkin, 2007) One review reported the NNT for at least moderate neuropathic pain relief with tricyclics is 3.6 (3-4.5), with the NNT for amitriptyline being 3.1 (2.5-4.2). The NNT for venlafaxine, calculated using 3 studies, was reported to be 3.1 (2.2-5.1). (Saarto-Cochrane, 2007) Another review reported that the NNT for 50% improvement in neuropathic pain was 2 to 3 for tricyclic antidepressants, 4 for venlafaxine, and 7 for SSRIs (Perrot, 2008).

Side-effect profile: Tricyclics are contraindicated in patients with cardiac conduction disturbances and/or decompensation (they can produce heart block and arrhythmias) as well as for those patients with epilepsy. For patients > 40 years old, a screening ECG is recommended prior to initiation of therapy. (Dworkin, 2007) (ICSI, 2007) They can create anticholinergic side effects of dry mouth, sweating, dizziness, orthostatic hypotension, fatigue, constipation, and urinary retention. (Finnerup, 2005) To minimize side effects, it is suggested that titration should be slow and based on the patient’s response. (Namaka, 2004) An alternative choice may be a SNRI. (Finnerup, 2005) (Sindrup, 2005) (Dworkin, 2007) The muscle relaxant cyclobenzaprine is closely related to the tricyclic antidepressants so caution is advised when using cyclobenzaprine. (FDA, 2011)

Dosing Information:

Amitriptyline: Neuropathic pain: The starting dose may be as low as 10-25 mg at night, with increases of 10-25 mg once or twice a week up to 100 mg/day. (ICSI, 2007) The lowest effective dose should be used (Dworkin, 2007). Fibromyalgia: One review recommended the following dosing regimen: Start with low doses, such as 5-10 mg 1-3 hours before bedtime. Dose may be increased by 5 mg at two-week intervals; final dose is dependent upon efficacy and patient tolerability to side effects. Doses that have been studied range from 25 to 50 mg at bedtime. (Goldenberg, 2007)

Selective serotonin and norepinephrine reuptake inhibitors (SNRIs):

Duloxetine (Cymbalta®): FDA-approved for anxiety, depression, diabetic neuropathy, fibromyalgia and chronic musculoskeletal pain. (FDA, 2010) Used off-label for neuropathic pain and radiculopathy. Duloxetine is recommended as a first-line option for diabetic neuropathy. (Dworkin, 2007) No high-quality evidence is reported to support the use of duloxetine for lumbar radiculopathy. (Dworkin, 2007) More studies are needed to determine the efficacy of duloxetine for other types of neuropathic pain.

Side effects: CNS: dizziness, fatigue, somnolence, drowsiness, anxiety (3% vs.2% for placebo), insomnia (8-13% vs. 6-7% for placebo). GI: nausea and vomiting (5-30%), weight loss (2%). Duloxetine can worsen diabetic control in some patients. It also causes sexual dysfunction. (Maizels, 2005)

Dosing: 60 mg once a day as an off-label option for chronic pain syndromes. Dosage adjustment may be required in patients with renal insufficiency.

Venlafaxine (Effexor®): FDA-approved for anxiety, depression, panic disorder and social phobias. Off-label use for fibromyalgia, neuropathic pain, and diabetic neuropathy.

Side-effect profile: CNS: (≥ 5%) drowsiness, weakness, dizziness, dry mouth, insomnia, nervousness/anxiety (13/6% vs. 6/3%), tremor, headache, seizures. GI: N&V, constipation, weight loss (2-18%). Pre-existing hypertension should be controlled. Cholesterol may be increased (5%). Sexual dysfunction has also been noted. (Maizels, 2005) (ICSI, 2007)

Dosing: Neuropathic pain (off-label indication): 37.5 mg once daily, increase by 37.5 mg per week up to 300 mg daily. (Maizels, 2005) (ICSI, 2007) Trial period: Some relief may occur in first two weeks; full benefit may not occur until six weeks. Withdrawal effects can be severe. Abrupt discontinuation should be avoided and tapering is recommended before discontinuation.

Bupropion (Wellbutrin®), a second-generation non-tricyclic antidepressant (a noradrenaline and dopamine reuptake inhibitor) has been shown to be effective in relieving neuropathic pain of different etiologies in a small trial (41 patients). (Finnerup, 2005) While bupropion has shown some efficacy in neuropathic pain there is no evidence of efficacy in patients with non-neuropathic chronic low back pain. (Katz, 2005) Furthermore, a recent review suggested that bupropion is generally a third-line medication for diabetic neuropathy and may be considered when patients have not had a response to a tricyclic or SNRI. (Dworkin, 2007)

Side-effect profile: Headache, agitation, insomnia, anorexia, weight loss

Dosing Information: Neuropathic pain (off-label indication): 100 mg once daily, increase by 100 mg per week up to 200 mg twice daily. (Maizels, 2005)

Selective serotonin reuptake inhibitors (SSRIs), a class of antidepressants that inhibit serotonin reuptake without action on noradrenaline, are controversial based on controlled trials. (Finnerup, 2005) (Saarto-Cochrane, 2005) It has been suggested that the main role of SSRIs may be in addressing psychological symptoms associated with chronic pain. (Namaka, 2004) More information is needed regarding the role of SSRIs and pain.

Side Effects: Bleeding: An association has been found between the use of SSRI antidepressants and gastrointestinal bleeding. This risk is increased with the concomitant use of ASA or NSAIDs. It is suggested that the increased risk for GI bleeding be discussed with patients that have other risks for GI bleeding. An association with increased intraoperative blood loss has also been found with SSRI use. (Movig, 2003) A treatment option for those at risk for bleeding includes switching to an antidepressant with a lower degree of inhibition of serotonin reuptake (Intermediate reuptake: venlafaxine, amitriptyline, imipramine, citalopram; Low reuptake: desipramine, doxepin, trazodone, bupropion, mirtazapine). SSRIs with the highest degree of inhibition of serotonin reuptake include paroxetine, sertraline, and fluoxetine. (Looper, 2007)

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