Chronic Pain Syndrome

The pathophysiology of chronic pain syndrome (CPS) is multifactorial and complex and still is poorly understood. Some authors have suggested that CPS might be a learned behavioral syndrome that begins with a noxious stimulus that causes pain. This pain behavior then is rewarded externally or internally. Thus, this pain behavior is reinforced, and then it occurs without any noxious stimulus. Internal reinforcers are relief from personal factors associated with many emotions (eg, guilt, fear of work, sex, responsibilities). External reinforcers include such factors as attention from family members and friends, socialization with the physician, medications, compensation, and time off from work.

Patients with several psychological syndromes (eg, major depression, somatization disorder, hypochondriasis, conversion disorder) are prone to developing CPS.

Various neuromuscular, reproductive, gastrointestinal (GI), and urologic disorders may cause or contribute to chronic pain. Sometimes multiple contributing factors may be present in a single patient.

In a study by Alonso-Blanco, a connection was found in women between the number of active myofascial trigger points (MTrPs) and the intensity of spontaneous pain, as well as widespread mechanical hypersensitivity. Nociceptive inputs from these MTrPs may be linked to central sensitization.[8]

A literature review by Gupta et al indicated that in chronic pain patients, primary sensorimotor structural and functional changes are more prominent in females than in males. Males and females differed with regard to the nature and degree of insula changes (with males showing greater insula reactivity), as well as in the extent of anterior cingulate structural changes and in reactivity to emotional arousal.[9]

Musculoskeletal disorders

Musculoskeletal disorders commonly associated with chronic pain include the following:

• Osteoarthritis/degenerative joint disease/spondylosis (see the image below)

  Osteoarthritis of the knee, Kellgren stage III.

• Rheumatoid arthritis (see the image below)

  T1-weighted sagittal magnetic resonance imaging (MRI) scan of the cervical spine in a patient with rheumatoid arthritis shows basilar invagination with cranial migration of an eroded odontoid peg. There is minimal pannus. The tip of the peg indents the medulla, and there is narrowing of the foramen magnum, due to the presence of the peg. Inflammatory fusion of several cervical vertebral bodies is shown.

• Lyme disease

• Reiter syndrome

• Disk herniation/facet osteoarthropathy

• Fractures/compression fracture of lumbar vertebrae

• Faulty or poor posture

• Fibromyalgia[10, 11, 12, 13, 14]

• Polymyalgia rheumatica

• Mechanical low back pain

• Chronic coccygeal pain

• Muscular strains and sprains

• Pelvic floor myalgia (levator ani spasm)

• Piriformis syndrome (see the image below)

  Nerve irritation in the herniated disk occurs at the root (sciatic radiculitis). In piriformis syndrome, the irritation extends to the full thickness of the nerve (sciatic neuritis).

• Rectus tendon strain

• Hernias (eg, obturator, sciatic, inguinal, femoral, spigelian, perineal, umbilical)

• Abdominal wall myofascial pain (trigger points)

• Chronic overuse syndromes (eg, tendonitis, bursitis)

Neurologic disorders

Neurologic disorders associated with chronic pain include the following:

• Brachial plexus traction injury

• Cervical radiculopathy

• Thoracic outlet syndrome

• Spinal stenosis (see the image below)

  Oblique view of the cervical spine demonstrates 2 levels of foraminal stenosis (white arrows) resulting from facet hypertrophy (yellow arrow) and uncovertebral joint hypertrophy.

• Arachnoiditis

• Metabolic deficiency myalgias

• Polymyositis

• Neoplasia of spinal cord or sacral nerve

• Cutaneous nerve entrapment in surgical scar

• Postherpetic neuralgia (shingles)[15, 16]

• Neuralgia (eg, iliohypogastric, ilioinguinal, or genitofemoral nerves)

• Polyneuropathies

• Polyradiculoneuropathies

• Mononeuritis multiplex

• Chronic daily headaches

• Muscle tension headaches

• Migraine headaches

• Temporomandibular joint dysfunction

• Temporalis tendonitis

• Sinusitis

• Atypical facial pain

• Trigeminal neuralgia

• Glossopharyngeal neuralgia

• Nervus intermedius neuralgia

• Sphenopalatine neuralgia

• Referred dental or temporomandibular joint pain

• Abdominal epilepsy

• Abdominal migraine

• Stroke (central poststroke pain)[17]

Urologic disorders

Urologic disorders associated with chronic pain include the following:

• Bladder neoplasm

• Chronic urinary tract infection

• Interstitial cystitis

• Radiation cystitis

• Recurrent cystitis

• Recurrent urethritis

• Urolithiasis

• Uninhibited bladder contractions (detrusor-sphincter dyssynergia)

• Urethral diverticulum

• Chronic urethral syndrome

• Urethral carbuncle

• Prostatitis

• Urethral stricture

• Testicular torsion

• Peyronie disease

Gastrointestinal disorders

GI disorders associated with chronic pain include the following:

• Chronic visceral pain syndrome

• Gastroesophageal reflux

• Peptic ulcer disease

• Pancreatitis

• Chronic intermittent bowel obstruction

• Colitis (see the image below)

  Severe colitis noted during colonoscopy. The mucosa is grossly denuded, with active bleeding noted. This patient had her colon resected very shortly after this view was obtained.

• Chronic constipation

• Diverticular disease

• Inflammatory bowel disease

• Irritable bowel syndrome

Reproductive disorders (extrauterine)

Extrauterine reproductive disorders associated with chronic pain include the following:

• Endometriosis (see the image below)

  Active endometriosis with red and powder-burn lesions; adhesions from old scarring are present.

• Adhesions

• Adnexal cysts

• Chronic ectopic pregnancy

• Chlamydial endometritis or salpingitis

• Endosalpingiosis

• Ovarian retention syndrome (residual ovary syndrome)

• Ovarian remnant syndrome

• Ovarian dystrophy or ovulatory pain

• Pelvic congestion syndrome

• Postoperative peritoneal cysts

• Residual accessory ovary

• Subacute salpingo-oophoritis

• Tuberculous salpingitis

Reproductive disorders (uterine)

Uterine reproductive disorders associated with chronic pain include the following:

• Adenomyosis

• Chronic endometritis

• Atypical dysmenorrhea or ovulatory pain

• Cervical stenosis

• Endometrial or cervical polyps

• Leiomyomata

• Symptomatic pelvic relaxation (genital prolapse)

An intrauterine contraceptive device can also be associated with chronic pain.

Psychological disorders

Psychological disorders associated with chronic pain include the following:

• Bipolar personality disorders

• Depression

• Porphyria

• Sleep disturbances

Other

The following disorders can also be associated with chronic pain:

• Cardiovascular disease (eg, angina)

• Peripheral vascular disease

• Chemotherapeutic, radiation, or surgical complications

Fibromyalgia risk

Results from a study by Mork et al indicated that women who are overweight or obese have a 60-70% greater risk of developing fibromyalgia than do women of normal weight, with body mass index (BMI) being an independent risk factor for the condition. The report looked at whether physical exercise and high BMI influence the occurrence of fibromyalgia. The study included 15,990 women, none of whom at baseline had fibromyalgia or any other physical impairment. By 11-year follow-up, incident fibromyalgia had reportedly occurred in 380 women. The authors noted that only a weak association typically existed between exercise level and fibromyalgia risk.

In overweight or obese women in the study who exercised for at least 1 hour each week, the relative risk (RR) for fibromyalgia (in comparison with women of normal weight and a similar activity level) was 1.72, while in overweight or obese women who did not exercise or who did so for less than an hour per week, the RR was 2.09.[10]

The patient and family should have a good understanding about the multifactorial nature of chronic pain and the benefits of a multidisciplinary comprehensive management plan.[6]

The patient should avoid uncomfortable stressful positions and bad posture. In addition, regular exercise, good sleeping habits, and balanced meals are helpful in maintaining good health. The patient may also benefit from instruction in biofeedback and relaxation techniques.

For excellent patient education information, see the Mental Health Center, as well as Chronic Pain, Fibromyalgia, Chronic Fatigue Syndrome (CFS), and Pain Medications.

Because of the complex etiology and the frequent presence of associated disorders, a general and open-minded approach to the assessment of the patient is needed. Obtaining the history of patients whose symptoms suggest chronic pain syndrome (CPS) is important. A thorough history is necessary for the physician to direct further evaluation and appropriate consultations and to avoid repeating invasive and expensive procedures.

A detailed review of the musculoskeletal, reproductive, GI, urologic, and neuropsychological systems must be obtained. As needed, specific questions should be asked of particular patients, depending on their associated disorders.

Focus the history on a characterization of the patient's pain. Obtaining the characteristics of the pain helps to establish appropriate diagnostic and therapeutic plans.

• Pain location - The location of pain is an important part of the history; ask the patient to describe the type of pain and the location on a pain diagram (anterior/posterior and lateral view of human picture)

• Precipitating factors - Ask questions about factors that provoke or intensify pain; this information may provide clues concerning possible etiologies or associated disorders

• Alleviating factors - Ask the patient if any factors help to alleviate the pain; for example, rest may decrease pain of musculoskeletal origin

• Quality of pain - Ask the patient to describe the quality of pain; various terms can be used to describe the quality of pain, including throbbing, pounding, shooting, pricking, boring, stabbing, lancinating, sharp, cutting, lacerating, pressing, cramping, crushing, pulling, pinching, stinging, burning, splitting, penetrating, piercing, squeezing, and dull aching

• Radiation of pain - Ask the patient if the pain spreads or radiates; spreading or radiating pain is a characteristic of neuropathic pain

• Severity or intensity of pain - Use some type of rating system to evaluate pain severity or intensity with a degree of objectivity and reproducibility; different types of pain scales may be used, with numerical scales being more useful and reliable (the visual analog scale [VAS] is one of the commonly used numerical scales)

The Pain Sensitivity Questionnaire can be used to measure general pain perception (pain perception outside the clinical pain site) in patients with chronic pain.[18]

A 2012 meta-analysis indicates that athletes exhibit higher pain tolerance than normally active subjects, suggesting that regular physical activity is associated with alterations in the perception of pain.[19]

Obtain history specific to the following systems and related disorders:

• Musculoskeletal

• Neurologic

• Gynecologic and obstetric

• Urologic

• GI

In addition, a good psychosocial or psychosexual history is needed when organic diseases are excluded or coexisting psychiatric disorders are suggested. Obtain sufficient history to evaluate depression; anxiety disorder; somatization; physical or sexual abuse; drug abuse/dependence; and family, marital, or sexual problems. Somatization is a commonly associated psychologic disorder in women with chronic pain. Somatization scales can be used for evaluation.[20]

A report by Nygaard et al on women with chronic pelvic pain found that those patients in the study who had been subject to abuse had a greater tendency toward analgesic use, obstructed defecation syndrome, anxiety, and subjective health complaints.[21]

Sternbach's 6 D 's of CPS are as follows:

• Dramatization of complaints

• Drug misuse

• Dysfunction/disuse

• Dependency

• Depression

• Disability

A literature review by Ravat et al indicated that in persons with chronic pain—specifically, complex regional pain syndrome type 1, upper limb pain, hand and wrist pain, carpal tunnel syndrome, facial pain, knee osteoarthritis, or leg pain—laterality judgement is impaired.[22]

Good rapport, tolerance, and an open-minded approach are important when evaluating any patient with chronic pain. A thorough systematic examination usually leads to an appropriate diagnosis and therapy. Patients often have Waddell signs. The disability is usually out of proportion to the impairment and the objective findings.

A patient with chronic pain syndrome (CPS) may exhibit exaggerated pain behavior. Sensations may seem to be hysterical or appear nonanatomic or nonphysiologic, but the patient always should be taken seriously and appropriate conservative steps should be taken.

Detailed examination of the musculoskeletal system is important. Examination of various other systems (eg, GI, urologic, neurologic) also should be performed.

The decision to perform any laboratory or imaging evaluations is based on the need to confirm the diagnosis and to rule out other potentially life-threatening illnesses. Sometimes certain investigations are needed to provide appropriate and safe medical or surgical treatment. The recommended treatment should be based on clinical findings or changes in examination findings.

Extreme care should be taken during diagnostic testing for chronic pain syndrome (CPS). Carefully review prior testing to eliminate unnecessary repetition.

Routine complete blood count (CBC), urinalysis, and selected tests for suspected disease are important. Urine or blood toxicology is important for drug detoxification, as well as opioid therapy.

Imaging studies

Imaging studies, including with radiography, magnetic resonance imaging (MRI), and computed tomography (CT) scanning, are important tools in the workup of patients with CPS. (See the images below.)

Management of chronic pain in patients with multiple problems is complex, usually requiring specific treatment, simultaneous psychological treatment, and physical therapy (PT).[6, 7] A good relationship between the physician and patient should be established.

Treatment of chronic pain syndrome (CPS) must be tailored for each individual patient. The treatment should be aimed at interruption of reinforcement of the pain behavior and modulation of the pain response. The goals of treatment must be realistic and should be focused on restoration of normal function (minimal disability), better quality of life, reduction of use of medication, and prevention of relapse of chronic symptoms.

Psychological interventions, in conjunction with medical intervention, PT, and occupational therapy (OT), increase the effectiveness of the treatment program.[20] Family members are involved in the evaluation and treatment processes.

Appropriate caution must be taken during CPS treatment in patients who exhibit any of the following behaviors:

• Poor response to prior appropriate management

• Unusual, unexpected response to prior specific treatment

• Avoidance of school, work, or other social responsibility

• Severe depression

• Severe anxiety disorder

• Excessive pain behavior

• Physician shopping

• Noncompliance with treatment in the past

• Drug abuse or dependence

• Family, marital, or sexual problems

• History of physical or sexual abuse

Inpatient and outpatient care

Hospitalization usually is not required for patients with chronic pain syndrome, but it depends on how invasive the treatment choice is for pain control and on the severity of the case.

Patients with chronic pain syndrome generally are treated on an outpatient basis and require a variety of health care professionals to manage their condition optimally.

A self-directed or therapist-directed physical therapy (PT) program, individualized to the patient's needs and goals and provided in association with occupational therapy (OT), has an important role in functional restoration for patients with chronic pain syndrome (CPS).[7, 23, 24]

The goal of a PT program is to increase strength and flexibility gradually, beginning with gentle gliding exercises. Patients usually are reluctant to participate in PT because of intense pain.

PT techniques include hot or cold applications, positioning, stretching exercises, traction, massage, ultrasonographic therapy, transcutaneous electrical nerve stimulation (TENS), and manipulations. (According to a double-blind study, exercise groups have significant benefit over TENS.) Heat, massage, and stretching can be used to alleviate excess muscle contraction and pain. Other intervention should be offered to enable greater confidence and comfort when patients do not progress in a reasonable amount of time.

A prospective study by Masterson et al suggested that physical therapy using pelvic floor rehabilitation may offer an effective treatment for men with idiopathic chronic pelvic pain syndrome. Treatment response was considered robust in five out of 10 patients (50%), and moderate in two out of 10 (20%), with therapy involving the following[25] :

• Internal and external manual therapy of the pelvic floor and abdominal musculature to promote muscle relaxation
• Therapeutic exercises aimed at improving range of motion, mobility/flexibility, and muscle strength
• Biofeedback aimed at strengthening and relaxing the pelvic floor musculature
• Neuromodulation to relax the pelvic floor musculature and relieve pain

A literature review by Andrade et al did not find clear evidence regarding exercise’s impact on inflammatory markers in patients with fibromyalgia. However, none of the studies used in the report indicated that treatment-related exercises caused patients’ symptoms to worsen.[26]

A study by Grinberg et al of female patients with chronic pelvic pain syndrome indicated that myofascial physical therapy (MPT) is not only associated with long-lasting alleviation of pelvic pain, but also with anatomic, neurophysiologic, and psychological benefits. The investigators state that MPT leads to hypertonicity relief, reduction in sensitivity to experimental pain, improvement in endogenous inhibitory system functionality, and lowering of psychological distress (with regard to anxiety, pain catastrophizing, somatization, and depressive symptoms).[27]

A literature review by Haller et al indicated that in patients with chronic pain, craniosacral therapy (CST), which employs fascial palpation, is superior to sham treatment with regard to improvement in pain intensity and disability at 6 months. The study included patients with neck and back pain, migraine, headache, fibromyalgia, epicondylitis, and pelvic girdle pain.[28]

A randomized, controlled trial by Rodríguez Torres et al indicated that a neurodynamic mobilization program can reduce pain and fatigue and improve neurodynamics and function in patients with fibromyalgia. The study included 48 patients with fibromyalgia who were randomized to a twice-a-week active neurodynamic mobilization program or to a control group, with results evaluated using the Brief Pain Questionnaire, the Pain Catastrophizing Scale, neurodynamic tests, the Health Assessment Questionnaire Disability Index, and the Fatigue Severity Scale.[29]

A phase II, randomized, sham-controlled clinical trial by Mendonca et al indicated that the use of a combination of transcranial direct current stimulation (tDCS) of the primary cortex and aerobic exercise is more effective in managing in fibromyalgia than is either of these modalities by itself, having significantly impacted pain, anxiety, and mood. However, motor cortex plasticity response did not differ between the three groups, with the investigators suggesting that perhaps the combination of tDCS and aerobic exercise influenced other neural circuits.[30]

A literature review by Knijnik et al indicated that repetitive transcranial magnetic stimulation (rTMS) has a better effect on quality of life than does sham stimulation in patients with fibromyalgia, with the superior impact seen after 1 month of treatment. However, although reductions in pain intensity were found, changes in depressive symptoms were not.[31]

TENS

This therapy has significant benefit in the treatment of rheumatoid arthritis and osteoarthritis. Electrodes should be applied over or near the area of pain with the dipole parallel to major nerve trunks. TENS application should be avoided near the carotid sinus, during pregnancy, and in patients with demand-type pacemakers. The most common adverse effect of TENS is skin hypersensitivity.

Application of heat and cold

Use of these modalities is encouraged for the treatment of CPS, although the use of cold in neuropathic pain is controversial.

Occupational therapy (OT) is very important for initiating gentle, active measurements and preliminary desensitization techniques among patients who have chronic pain, especially regional chronic pain syndrome.

Recreational therapy can help the patient with chronic pain to take part in pleasurable activities that help to decrease pain. The patient finds enjoyment and socialization in previously lost recreational activities or in new ones. Usually, patients with chronic pain are depressed because of intense pain. Recreational therapists may play an important role in the treatment process as they help enable the patient to become active.

Vocational therapy should be recommended and initiated early for all appropriate patients. It can provide work capacities and targeted work hardening so that the patient may return to gainful employment, the ultimate functional restoration.

Each patient is evaluated to determine work history, educational background, vocational skills and abilities, and motivation level to return to work. The patient should get help from a vocational counselor regarding legal rights and obligations in each state (eg, workman's compensation). Each patient needs to set realistic goals.

Nerve blocks

Nerve blocks are used for diagnostic, prognostic, and therapeutic procedures. (Nerve block ̶ related anatomy is depicted below.) Sympathetic blocks, including stellate ganglion and lumbar sympathetic blocks, commonly are used and are more effective therapeutic tools for chronic pain.

Spinal cord stimulation

Spinal cord stimulation commonly is used to treat neuropathic pain refractory to other forms of treatment. Spinal cord stimulation also is used for patients with a failed back syndrome with radicular pain. Careful evaluation is recommended before patient selection for this treatment, including a preprocedure psychological/psychiatric evaluation, and a successful spinal cord stimulator trial is required prior to implantation of the stimulation device.

Intrathecal morphine pumps

Intrathecal morphine pumps, either fully implantable or external, are used to treat chronic pain. Use of these devices should be considered very carefully for pain of nonmalignant origin, with a preprocedure psychological/psychiatric patient examination being included in the evaluation. A successful intrathecal morphine pump trial is required prior to implantation of the pump.

Noninvasive brain stimulation

A literature review by Baptista et al yielded consensus recommendations on the use of noninvasive brain stimulation in the management of chronic pain in Latin America and the Caribbean region. These include the following, with the investigators specifying that low to moderate analgesic effects can be obtained in association with level A recommendations, while potential, but uncertain benefits, are associated with level B recommendations[32] :

• The use of anodal transcranial direct current stimulation (tDCS) over the primary motor cortex was recommended for the control of fibromyalgia pain (level A), as well as for peripheral neuropathic pain, abdominal pain, and migraine (level B)
• Bifrontal (F3/F4) tDCS and high-definition (HD) tDCS over the primary motor cortex were recommended for the treatment of fibromyalgia (level B)
• Occipital/top-of-the head (Oz/Cz) tDCS was recommended for migraine treatment (level B)
• High-frequency repetitive transcranial magnetic stimulation (HF rTMS) over the primary motor cortex was recommended for fibromyalgia and neuropathic pain (level A), as well as for myofascial pain, musculoskeletal pain, complex regional pain syndrome, and migraine (level B)
• A recommendation was made against the treatment of low back pain with primary motor cortex tDCS
• A recommendation was made against the treatment of chronic pain with HF rTMS over the left dorsolateral prefrontal cortex

Other

A study by Colini Baldeschi et al indicated that peripheral nerve stimulation can also effectively reduce chronic neuropathic pain resulting from a peripheral nerve lesion. In the study, patients in whom this condition had proven refractory to conventional surgical or pharmacologic treatment underwent peripheral placement of an implantable pulse generator near the stimulation site. By 6-month follow-up, 69% of these patients had experienced a reduction in the pain numeric rating scale of over 50%, while quality-of-life physical and mental indices in the study patients rose by 18% and 29%, respectively. In addition, 55% of patients no longer needed analgesic drugs, while 16% underwent a reduction of these agents.[33]

 

This type of therapy consists of reassurance, counseling, relaxation therapy, stress management programs, and biofeedback techniques. With these treatment modalities, the frequency and severity of chronic pain may be reduced.[20]

Biofeedback may be helpful in some patients when combined with medications, while behavioral techniques have been successfully used to treat myofascial and sympathetically mediated pain syndromes.

Relaxation training, including autogenic training and progressive muscle relaxation, commonly is used. This approach is as effective as biofeedback.

A randomized, controlled study by Wetherell et al determined that acceptance and commitment therapy (ACT) and cognitive-behavioral therapy (CBT) are effective treatments for chronic pain, positively affecting mood and pain interference. However, ACT may be more beneficial, since patients gave this treatment a higher satisfaction rating than CBT.[34]

In another randomized, controlled evaluation, researchers tested the efficacy of an online chronic pain management program using 305 adult participants with chronic pain. While 162 individuals used the program unsupervised for about 6 weeks, the other 143 people were assigned to the wait-listed control group with treatment as usual. A detailed assessment was conducted before the study and after about 7 and 14 weeks. Results indicated that those using the online program had significant decreases in pain severity, pain-related interference and emotional burden, perceived disability catastrophizing, and pain-induced fear. In addition, participants found that the online program lessened their depression, anxiety, and stress and gave them more information about chronic pain management.[35]

A study by O’Sullivan et al indicated that cognitive functional therapy can be effective in the management of nonspecific chronic low back pain. Patients in the study underwent approximately eight cognitive functional therapy treatments, with 1-year posttherapy follow-up. The subjects demonstrated significant improvements in functional disability and pain immediately after completing treatment and maintained these gains over the follow-up period.[36]

Consultation with a psychologist, a urologist, a neurologist, an obstetrician-gynecologist, a GI specialist, or other appropriate specialist is very important, especially before considering invasive or aggressive management of a patient with chronic pain syndrome (CPS).

The high incidence of personality pathology in CPS may represent an exaggeration of maladaptive personality traits and coping styles caused by chronic, intense pain. A psychological evaluation should be performed to identify the stressor and to obtain information about the distress of the patient. The evaluation should consist of a structural clinical interview and a personality measure (eg, Minnesota Multiphasic Personality Scale, Hopelessness Index).

Noninvasive brain stimulation

A literature review by Baptista et al yielded consensus recommendations on the use of noninvasive brain stimulation in the management of chronic pain in Latin America and the Caribbean region. These include the following, with the investigators specifying that low to moderate analgesic effects can be obtained in association with level A recommendations, while potential, but uncertain benefits, are associated with level B recommendations[32] :

• The use of anodal transcranial direct current stimulation (tDCS) over the primary motor cortex was recommended for the control of fibromyalgia pain (level A), as well as for peripheral neuropathic pain, abdominal pain, and migraine (level B)
• Bifrontal (F3/F4) tDCS and high-definition (HD) tDCS over the primary motor cortex were recommended for the treatment of fibromyalgia (level B)
• Occipital/top-of-the head (Oz/Cz) tDCS was recommended for migraine treatment (level B)
• High-frequency repetitive transcranial magnetic stimulation (HF rTMS) over the primary motor cortex was recommended for fibromyalgia and neuropathic pain (level A), as well as for myofascial pain, musculoskeletal pain, complex regional pain syndrome, and migraine (level B)
• A recommendation was made against the treatment of low back pain with primary motor cortex tDCS
• A recommendation was made against the treatment of chronic pain with HF rTMS over the left dorsolateral prefrontal cortex

Pharmacotherapy for chronic pain syndrome (CPS) consists of symptomatic abortive therapy (to stop or reduce the severity of the acute exacerbations) and long-term therapy for chronic pain. Initially, pain may respond to simple over-the-counter analgesics, such as paracetamol, ibuprofen, aspirin, or naproxen. If treatment is unsatisfactory, the addition of other modalities or the use of prescription drugs is recommended. If possible, avoid barbiturate or opiate agonists. Also, discourage long-term and excessive use of all symptomatic analgesics because of the risk of dependence and abuse.

In a longitudinal outcomes trial, researchers investigated 62 patients with CPS who were at low or high risk for opioid abuse. Researchers explored whether these patients had cravings for their medications, what influenced their cravings, and if a connection existed between craving and medication compliance. Patients noted their cravings at monthly clinic visits and daily during a 14-day period. Both the low- and high-risk groups regularly craved their medication, which was linked to urge, preoccupation, and mood. Focusing on cravings may help correct misuse and better assist with prescription opioid compliance.[37]

A study by W Guite et al evaluated the rates of medication use by adolescents with chronic musculoskeletal pain syndromes prior to first visiting a multidisciplinary clinic, determining that in 70% of these patients, more than one pain-specific medication was used. Regarding these drugs, the use rate for opioids was 17%; for nonopioids, 31%; for psychotropics/neuropathics, 45%; and for other medications, 13%.[38]

Tizanidine may improve the inhibitory function in the central nervous system (CNS) and can provide pain relief. Amitriptyline (Elavil) and nortriptyline (Pamelor) are the tricyclic antidepressants (TCAs) most frequently used to treat chronic pain. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft), as well as the selective serotonin/norepinephrine reuptake inhibitor (SNRI) duloxetine (Cymbalta), are commonly prescribed by many physicians. Other antidepressants, such as doxepin, desipramine protriptyline, and buspirone, also can be used.

A French study found evidence that botulinum toxin type A (BoNT-A) has direct analgesic effects when administered to patients with chronic neuropathic pain (performing actions that are independent of its effect on muscle tone).[39] Consequently, the study's authors suggested that BoNT-A may have "novel indications" in analgesia.

Kroenke et al found that a combination of pharmacologic and behavioral intervention were more effective than conventional therapy in the treatment of patients suffering from depression and chronic pain.[4] Patients (n=250) with low back, hip, or knee pain for 3 months or longer who also had moderate depression were randomly assigned to the combination therapy or usual care. Combination therapy consisted of optimized antidepressant therapy (12wk), followed by intervention for pain in a self-management phase (12wk), and a continuation phase (6 mo).

Depression improved in 37.4% of the combination therapy group (ie, 50% or greater reduction in depression), but in only 16.5% of the usual-care group (16.5%). Pain severity was reduced by 30% or more in 41.5% of the combination group, compared with 17.3% of the usual-care group.

A study by Gianni et al looked at the buprenorphine transdermal delivery system (BTDS) for its effect on chronic, noncancer pain. While the specific aim of this study was to examine cognitive and functional scores in an elderly population treated with the BTDS, a secondary finding related to its use was the effective analgesic activity and safety of BTDS in elderly patients. There was an improvement in mood and a partial resumption of activities, with no influence on cognitive and behavioral ability.[40]

A 2011 study determined that predictive factors for switching to higher-dose transdermal fentanyl in patients with cancer pain who were previously taking either oral morphine or oxycodone were breast cancer, total protein value, alanine aminotransferase value, older age, and male sex.[41]

A small randomized, double-blind, placebo-controlled trial by Weizman et al on the use of tetrahydrocannabinol (THC, the psychoactive component of cannabis) in the treatment of chronic neuropathic pain suggested that the agent induces pain reduction by decreasing functional connectivity between the anterior cingulate cortex and the sensorimotor cortex.[42, 43]

Class Summary

These agents increase the synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibiting their reuptake by the presynaptic neuronal membrane.

Amitriptyline

Amitriptyline is an analgesic for certain chronic and neuropathic pain.

Nortriptyline (Pamelor)

Nortriptyline has demonstrated effectiveness in the treatment of chronic pain. By inhibiting the reuptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane, this drug increases the synaptic concentration of these neurotransmitters in the CNS. Pharmacodynamic effects such as the desensitization of adenyl cyclase and down-regulation of beta-adrenergic receptors and serotonin receptors also appear to play a role in its action.

Duloxetine (Cymbalta)

Duloxetine is indicated for diabetic peripheral neuropathic pain. It is a potent inhibitor of neuronal serotonin and norepinephrine reuptake.

Venlafaxine (Effexor, Effexor XR)

Venlafaxine inhibits neuronal serotonin and norepinephrine reuptake. In addition, it causes beta-receptor down-regulation. Venlafaxine may decrease neuropathic pain and help with sleep and other mood disorders (depression or depressive symptoms).

Fluoxetine (Prozac)

Fluoxetine is an atypical non ̶ tricyclic antidepressant (non-TCA) with potent specific 5HT-uptake inhibition and fewer anticholinergic and cardiovascular adverse effects than TCAs. Consider this drug as an alternative to TCAs.

Sertraline (Zoloft)

Sertraline is an atypical non-TCA with potent specific 5HT-uptake inhibition and fewer anticholinergic and cardiovascular adverse effects than TCAs. Consider it as an alternative to TCAs.

Paroxetine (Paxil, Pexeva)

Paroxetine is an atypical non-TCA with potent specific 5HT-uptake inhibition and fewer anticholinergic and cardiovascular adverse effects than TCAs. Consider it as an alternative to TCAs.

Class Summary

Certain antiepileptic drugs (eg, the gamma-aminobutyric acid [GABA] analogue gabapentin and pregabalin [Lyrica]) have proven helpful in some cases of neuropathic pain.[15] For example, a randomized, double-blind, placebo-controlled study reported that twice-daily doses of gastric-retentive, extended-release gabapentin (gabapentin ER) provided safe and effective treatment for postherpetic neuralgia; nonplacebo patients in the study received 1800 mg of gabapentin per day.[16]

Pregabalin also demonstrated pain relief in diabetic peripheral neuropathy and postherpetic neuralgia. It may provide benefit in other neuropathic pain as well.[44]

A Cochrane Database of Systematic Reviews article that looked at 29 studies with a total of 3571 participants with chronic pain conditions concluded that gabapentin provided pain relief in about 30% of patients. Adverse events, although frequent, were mostly tolerable; they included dizziness, somnolence, peripheral edema, and gait disturbance.[45]

Other anticonvulsant agents (eg, clonazepam, topiramate, lamotrigine, zonisamide, tiagabine) also have been tried in chronic pain syndrome (CPS).

Gabapentin (Neurontin)

Gabapentin has anticonvulsant properties and antineuralgic effects; however, its exact mechanism of action is unknown. It is structurally related to GABA but does not interact with GABA receptors.

Pregabalin (Lyrica)

Pregabalin is a structural derivative of GABA; its mechanism of action unknown. Pregabalin binds with high affinity to the alpha2-delta site (a calcium channel subunit), and in vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. The US Food and Drug Administration (FDA) approved it for the treatment of neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures.

Class Summary

Analgesics are commonly used for many pain syndromes. Pain control is essential to quality patient care. Analgesics ensure patient comfort, promote pulmonary toilet, and have sedating properties, which are beneficial for patients who have sustained traumatic injuries.

Oxycodone (OxyContin, Roxicodone)

Long-acting opioids may be used in patients with CPS. Start with a small dose and, if appropriate, gradually increase it.

Fentanyl (Duragesic, Fentora, Onsolis, Actiq)

Fentanyl is a potent narcotic analgesic with a much shorter half-life than morphine sulfate. It is the drug of choice for conscious-sedation analgesia. Fentanyl is ideal for analgesic action of short duration during anesthesia and during the immediate postoperative period. It is an excellent choice for pain management and sedation of short duration (30-60min).

Fentanyl is easy to titrate and is easily and quickly reversed by naloxone. When the transdermal dosage form is used, most patients achieve pain control with 72-hour dosing intervals; however, some patients require dosing intervals of 48 hours.

Acetaminophen (Tylenol, FeverAll, Aspirin Free Anacin)

Acetaminophen is the drug of choice for the treatment of pain in patients with documented hypersensitivity to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs), with upper GI disease, who are pregnant, or who are taking oral anticoagulants.

Class Summary

NSAIDs have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclo-oxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

Ibuprofen (Motrin, Advil, Addaprin, Caldolor)

Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Naproxen sodium (Anaprox, Naprelan, Naprosyn, Anaprox)

This agent is used for the relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which results in a decrease in prostaglandin synthesis.

Diclofenac (Voltaren, Cataflam XR, Zipsor, Cambia)

Diclofenac inhibits prostaglandin synthesis by decreasing COX activity, which, in turn, decreases formation of prostaglandin precursors.

Indomethacin (Indocin)

Indomethacin is thought to be the most effective NSAID for the treatment of ankylosing spondylitis, although no scientific evidence supports this claim. It is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

Ketoprofen

Ketoprofen is used for relief of mild to moderate pain and inflammation. Small dosages are indicated initially in small patients, elderly patients, and patients with renal or liver disease. Doses higher than 75 mg do not increase the therapeutic effects. Administer high doses with caution, and closely observe the patient's response.