Pain

Clinical Bulletin
Information for Health Professionals
Pain in Multiple Sclerosis
by Heidi Maloni, DNScc, RN, APRN, BC-ANP, CNRN, MSCN
INTRODUCTION
Pain is a recognized symptom of multiple sclerosis (MS), affecting as many as seventy-five percent of people at some time during the course of their disease.1–4 However, only twenty- five percent of those who suffer with MS pain are being treated for it—presumably because painis more difficult to manage than other MS symptoms.5 Pain is a subjective sensory experience:“Pain is whatever the experiencing person says it is, existing whenever he/she says it does.”6 Thesubjective nature of pain, coupled with the different causal mechanisms seen in MS, contributeto the treatment challenge.
The most commonly reported pain syndromes in MS are burning dysesthesias in the lowerextremities, headache, lower back pain, and painful spasms.1–2 People with MS describe theirpain as having varying levels of severity and intensity, and characterize it as sharp, shooting,dull, or nagging pain that is either continuous or intermittent.7 Compared to the various typesof pain described by the general population, the pain experienced by people with MS isreported as more intense, having greater impact on activities of daily living, and requiringgreater use of analgesia.2–4,8–11 The symptom of pain in MS demands attention, as it impacts activities of daily living and isassociated with anxiety, depression, and fatigue.8 Pain in MS is also, but not exclusively,associated with longer disease duration, advancing age, higher disability scores, and secondary-progressive disease course.2,4,8–11 CLASSIFICATION OF MS PAIN
The etiology of MS pain is mixed. MS pain can be classified as either neurogenic (central) in originor nociceptive (secondary to other factors). Whereas neurogenic pain is a consequence of lesions inthe central nervous system (CNS), nociceptive pain is associated with noxious thermal, mechanical,electrical, or chemical stimuli that are generally a consequence of disease-related disability Tel: 1-866-MS-TREAT (678-7328)E-mail: MD_info@nmss.org A Clinical Bulletin from the Professional Resource Center of the National Multiple Sclerosis Society rather than the disease process itself.1,12–15 Differentiating types of MS-related pain according tothe causal mechanism involved facilitates mechanism-tailored treatment strategies.12, 16 Neurogenic Pain
Neurogenic pain results from lesions in the CNS.15 The neurogenic pain syndromes described inMS include: trigeminal neuralgia; glossopharyngeal neuralgia; painful tonic seizures or spasms;dysesthesias of the extremities; thoracic and abdominal band-like sensations; certain types ofheadache; episodic facial pain; Lhermitte’s sign; and paroxysmal limb pain.
Neurogenic pain is further described by the character, duration, and intensity of symptoms thatare experienced. Neurogenic pain often occurs spontaneously—i.e., independent of any stimulus—and may be either paroxysmal or continuous. Spontaneous paroxysmal pain is typically characterizedas shooting, stabbing, shock-like, lancinating, crushing, or searing. The most common forms ofspontaneous continuous pain are dysesthesias—abnormal sensations that are characterized asburning, aching, prickling, tingling, nagging, dull and/or band-like. Dysesthesias are typically lessintense than paroxysmal episodes of pain.4,12 Stimulus-dependent forms of neuropathic pain (i.e., occurring in reaction to a stimulus) includepainful spasms and allodynia. Allodynia refers to pain in response to a stimulus that does notnormally cause pain, such as gentle touch, massage, the feeling of clothing against the skin, orthe weight of bed covers. Stimulus-dependent pain is usually of short duration and normallylasts only for the period of the stimulus.12,15 The following is a review of the most common neuropathic pain syndromes seen in MS: ◆ Paroxysmal Pain Syndromes
◆ Trigeminal Neuralgia. Trigeminal neuralgia (TN) is a spontaneous neurogenic pain
experienced by approximately 4% of the MS population (a prevalence 400 times greaterthan in the general population). It affects one or more branches of the trigeminal nervethat innervates the eye, cheek, and jaw. TN is an intense, severe, sharp, electric-shocklike pain, which is generally unilateral but may occasionally present bilaterally.17Attacks can be spontaneous, or may be triggered or worsened by touching, chewing,smiling, or any facial movement. Periods in which sharp, shock-like attacks lasting 2 to3 seconds to several minutes occur at varying frequency are typically interspersed withperiods of remission. In rare instances the individual experiences episodes of longerduration (45–60 min) or continuous pain. TN rarely occurs during sleep.18 The onset ofTN in MS occurs at an earlier age than in the general population. Presentation of TNpain in young adults may be diagnostic of MS.19 TN in MS is thought to be associated with a lesion at the trigeminal root entry zone of the pons.20 Interrupting the pain pathway is the mechanism-tailored treatment strategyfor trigeminal neuralgia in MS. Anticonvulsant medications, known to stabilize cellmembranes—thereby decreasing the hyperexcitability of sensory neurons via sodiumand calcium channel regulation—are the first-line treatment for the pain of trigeminal A Clinical Bulletin from the Professional Resource Center of the National Multiple Sclerosis Society neuralgia.21–22 The second generation anticonvulsant agents have gentler side effectprofiles; sustained-release, long-acting formulas minimize side effects.
When pain relief is not obtained through drug intervention, surgical gamma knife, radiofrequency, or nerve block procedures that interrupt the pain pathway may becomean option. Percutaneous radiofrequency or glycerol rhizotomy is a safe and effective treat-ment, with lower reported risk of facial sensory loss than other invasive therapies.23–25 ◆ Headache. Headache is more common in MS than in the general population, with 58%
of patients experiencing episodic headache pain.26 Although the relationship betweenMS and headache is not clear, MS lesions in the midbrain have been associated withmigraine-type headache.27 The headaches in MS are usually characterized as migraine-like, cluster, or tension-type. Migraine headache is more commonly reported in patientswith relapsing-remitting disease. There is some evidence that migraine headaches areassociated with exacerbation of MS symptoms.26 Headaches should be treated following existing clinical guidelines for headache type. Mechanism-based treatment strategies include increasing the availability of theneurotransmitters serotonin and norepinephrine. The tricyclic antidepressants and theserotonin and norepinephrine reuptake inhibitors have been used with success in somepatients. Increasing the availability of serotonin and norepinephrine may be an effectiveongoing therapy for MS patients experiencing headache, as migraine is linked to changesin serotonin function and MS patients may have low serotonin levels.28 ◆ Continuous Pain Syndromes
◆ Dysesthetic Pain. The most common type of continuous pain experienced in MS is
dysesthetic pain, which is defined as an unpleasant, abnormal sensation that is eitherspontaneous or evoked.15 Dysesthetic pain occurs more commonly in people withminimal disability and is characterized by sensations described as burning, prickling,or tingling, nagging, dull, or band-like.1,7 This persistent pain—often symmetric—typically affects the legs and feet but may also involve the arms, trunk, and perineum(called vulvodynia). Although dysesthetic pain is usually of moderate intensity, itsnagging, persistent nature makes it difficult to tolerate. It is typically worse at night, andtends to be aggravated by changes in temperature. Dysesthetic pain can be associatedwith feelings of warmth or cold in the extremities that are unrelated to actual tempera-ture.29 Allodynia is considered the hallmark of stimulus-induced dysesthetic pain. Theuse of a bed cradle and lambskin pads or booties may offer relief.
Dysesthetic pain is difficult to treat fully. Mechanism-based strategies include neuromodulation and interruption of pain pathways, with tricyclic antidepressantsconsidered the first-line treatment. There is recent evidence that combination therapy(anticonvulsants plus antidepressants) provides greater effect with lower doses andfewer side effects.30,31 Topical agents such as capsaicin (Zostrix®), applications of heatand cold, and transdermal agents such as clonidine gel or patch (Catapres-TTS®) andthe lidocaine patch (Lidoderm®) are effective management strategies. In the absenceof allodynia, stimulation with fitted prescription pressure stockings at night, massage,acupuncture, or transcutaneous electric nerve stimulation (TENS), can also offer relief.21 A Clinical Bulletin from the Professional Resource Center of the National Multiple Sclerosis Society Nociceptive Pain
While nociceptive pain can be acute or chronic, the most common experiences in MS arechronic. This type of pain tends to be associated with greater disability and specifically describedas low back pain and pain resulting from severe spasticity.1,2,32 Nociceptive pain can be intermit-tent or continuous, provoked or spontaneous. Some nociceptive pain can be easily localized—often described as aching, squeezing, stabbing or throbbing. Other nociceptive pain is morevariable in intensity and not as well localized—generally described as gnawing or cramping,although sometimes described as sharp.
◆ Musculoskeletal Pain
Common nociceptive pain experiences in MS, including back pain and painful spasms,involve the musculoskeletal system. MS musculoskeletal pain is a result of weakness,deconditioning, immobility, and stress on bones, muscles, and joints. Steroid use con-tributes to osteoporosis and possible compromise of the blood supply to large joints(avascular necrosis), with associated pain. Any pain of a musculoskeletal nature requiresa thorough assessment for lumbar disc disease, avascular necrosis, or other condition.
Prevention is critical to the management of musculoskeletal pain. Bone antiresorptive therapies (e.g., calcitonin (Miacalcin®), alendronate (Fosamax®), raloxifene (Evista®),teriperatide (Forteo®)), smoking cessation, and calcium and vitamin D supplementationare preventive for pain associated with osteoporosis.
Physical therapy is essential for assessment and management of safety, gait, positioning, seating, and effective use of mobility aids, and ankle-foot-orthoses. Exercise and weightcontrol are effective in preventing and treating musculoskeletal pain. Frequent positionchange and proper support relieve stress on muscles, bones, and joints.
Acetaminophen (Tylenol®), salicylates (aspirin), and nonsteroidal anti-inflammatory agents (NSAIDs) such as ibuprofen (Motrin®), naproxen (Aleve®), and celecoxib (Celebrex®)are first line medical treatments for musculoskeletal pain. All types of NSAIDs can causeGI irritation and bleeding, They can also decrease renal blood flow, causing fluid retentionand hypertension. NSAID labeling includes a black box warning for the potential risk ofcardiovascular events and life-threatening GI bleeding. The U.S. Federal Drug Administra-tion recommends that NSAIDs be dosed exactly as prescribed or listed on the label. Thelowest possible dose should be given for the shortest possible time.33 ◆ Spasticity
Flexor and extensor muscle cramping, pulling, and subsequent pain occurs as spasticityin MS. Spasticity is evoked by noxious stimulation such as a decubitus ulcer, urinarytract infection, full bowel or bladder, or can result spontaneously from a CNS lesion.
Management of spastic pain in MS follows standard spasticity medication managementwith baclofen (Lioresol®), tizanidine (Zanaflex®), diazepam (Valium®), dantrolene(Dantrium®), or botulinum toxin (Botox®).
A Clinical Bulletin from the Professional Resource Center of the National Multiple Sclerosis Society MS PAIN MANAGEMENT
Management of pain in multiple sclerosis involves a combination of behavioral, physical, surgical,and medical interventions.32 Behavioral Mechanisms
Cognitive/behavioral approaches to MS pain management include education, relaxation, behaviormodification, distraction, psychotherapy, support groups, imagery, hypnosis, biofeedback,recreation, laugh therapy, music therapy, and, meditation.
Physical Mechanisms
Physical modalities include: physical therapy; stretching; application of heat, cold, and pressure;reconditioning to improve strength, endurance and flexibility; counter irritation; massage;acupuncture; exercise; yoga and Tai Chi; attention to ergonomics and positioning; electroanalgesiasuch as transcutaneous electric nerve stimulation (TENS); and, sound nutrition and weight control.
Medication Management
◆ Neurogenic Pain
Neurogenic pain is often resistant to therapy, requiring an in-depth and ongoing assessmentof pain indicators, sleep, mood, and quality of life. Medication management includes topicalagents, anticonvulsants, antidepressants, antiarrhythmics, NMDA-receptor antagonists, andnon-narcotic and narcotic opioids.16,21–22 The use of opioids in neurogenic pain remains controversial as studies show equivocal results.34 A meta-analysis of several randomized controlled trials demonstrated significantefficacy of opioids over placebo for non-MS neurogenic pain.35 Rowbotham and colleagues(2003) randomized eight MS patients to either high-dose or low-dose levorphanol andfound a significant effect of the high-dose opioid on pain intensity.36 Opioids should beconsidered when other agents become ineffective or are not well tolerated.37 Clearly,further studies are needed to confirm their long-term efficacy and safety for the treatmentof neurogenic pain in MS.
In April 2005, Health Canada, the drug regulatory agency for Canada, approved the use of the cannabis-derived drug Sativex® (GW Pharmaceuticals) to treat MS-related pain. Theapproval was based on a four-week clinical trial conducted in the United Kingdom in 66people with MS.38 Sativex contains extracts from the marijuana plant and is administeredas a spray into the mouth. This drug is not approved in the United States. Studies of theherbal cannabis, Delta(9)-tetrahydrocannabinol, and the oral form dronabinol (Marinol®)indicate a modest analgesic effect on MS pain.39 Current studies have been short-termand the long-term adverse events of cannabinoid use in MS have not been determined.
Modest therapeutic effect must be balanced with disruption in cognitive function, andincreases in anxiety and depression.40 A Clinical Bulletin from the Professional Resource Center of the National Multiple Sclerosis Society The goal of pain management is to enhance comfort, function, mood, sleep, and qual- ity of life. The benefits of the medications used must be weighed against their sideeffects. The use of combination therapy (low doses of different drug classes and differentdrugs within classes) may increase efficacy while minimizing the unwanted effects.
◆ Nociceptive Pain
Medications commonly used to manage nociceptive pain include acetaminophen, salicylatesand nonsteroidal anti-inflammatory agents, and non-narcotic and narcotic opioids.
Table 1 (see pp. 7–8) provides information about the medications commonly used to manage neurogenic/neuropathic pain in MS, including dosage, adverse events, andindications for use. The indications for medication use are derived primarily from evidence-based trials in diabetic and post-herpetic neuropathy.
Invasive Interventions
Invasive procedures include intrathecal medication administration of either baclofen (Lioresol®)or morphine, or both in combination; botulinum toxin (Botox®) injection; phenol injection oftrigger-points; epidural steroids; regional blocks; spinal cord stimulators; and various surgicalprocedures.
◆ Deep brain stimulation, which generates a pulse to relieve pain through electrodes planted in the brain, has the advantage of being reversible.
◆ Neurosurgical procedures include: cordotomy, rhizotomy, percutaneous balloon compression, percutaneous glycerol injection, radiofrequency rhizotomy, and Gammaknife radiosurgery. Microvascular decompression surgery (MVD) has not shown aneffect that outweighs side effects for pain in MS.41 ◆ Neuroablative techniques are considered when medical therapy is not well tolerated or is ineffective in managing pain. Quality of life is balanced with possible adverse effects oflocalized numbness, pain recurrence, and possible worsening of the underlying pain.18 Pain control is an achievable goal that begins with a thorough assessment, including theidentification of pain triggers. Recommendations for effective pain management include: ◆ Use preventive measures and non-drug strategies in conjunction with medications.
◆ Be familiar with the treatment options and side effects—and treat the side effects ◆ Use low doses of several different medications to achieve greater efficacy with fewer ◆ Begin with low doses and titrate slowly to an effective pain control. If pain free for three months, titrate back the dosage slowly.
A Clinical Bulletin from the Professional Resource Center of the National Multiple Sclerosis Society Pharmacological Treatment of Neurogenic/Neuropathic Pain in MS
Class of Medication
Use in Multiple Sclerosis
Antidepressants
Chronic neurogenic pain (e.g., dysesthetic extremity pain such asburning, tingling); often prescribed at night, but split dosing is recommended ◆ Tricyclic Antidepressants
◆ amitriptyline (Elavil®)◆ imipramine (Tofranil®)◆ desipramine (Norpramine®)◆ nortriptyline (Pamelor®) ◆ SNRI Antidepressants
Migraine; episodic and continuous neurogenic pain (sharp, shooting, Antiepileptics
For use primarily in sharp, lancinating neurogenic pain (e.g., trigeminalneuralgia); also used in dull or burning, continuous neurogenic pain Trigeminal neuralgia; tonic painful seizures; pelvic pain; intense Trigeminal neuralgia; pins/needles sensations; cramping; dysestheticextremity pain; tonic spasms; nocturnal spasms. Good combinationdrug with little drug-drug interaction; better tolerated than carba-mazepine Same indications as gabapentin; better tolerated with lower effectivedoses Trigeminal neuralgia; continuous and episodic dysesthetic extremitypain; burning; painful tonic spasms. Better tolerated than carba-mazepine Trigeminal neuralgia; sharp, episodic paroxysmal pain Antiarrhythmic Agents
Neurogenic pain; painful tonic seizures; trigeminal neuralgia; itching,Lhermitte’s Not well tolerated; use as add-on therapy A Clinical Bulletin from the Professional Resource Center of the National Multiple Sclerosis Society Continued
Class of Medication
Use in Multiple Sclerosis
Transdermal Agents
Moderate, continuous dysesthetic neurogenic pain. Use to reduce oralmedication load or side effects Use for neurogenic, dysesthetic, continuous, burning, tingling pain ofrecent onset. Less effective for long-term and severe dysesthetic pain Mild/moderate neurogenic/nociceptive pain Moderate neurogenic/nociceptive pain not responsive to non-opioid Antispasmodic Agents
Painful spasticity; trigeminal neuralgia; glossopharyngeal neuralgia Nonsteroidal Antiinflammatories
Nociceptive pain (ineffective for neurogenic pain) (NSAIDs)
(selective representation)
◆ ibuprofen (Motrin®; Advil®)◆ naproxyn sodium (Naprosyn®; ◆ celecoxib (Celebrex®)◆ aspirin (ASA) Non-Opioid and Opioid Agents
Use as add-on for moderate/severe neurogenic/nociceptive pain, orwhen non-opioids are ineffective—caution in combination with carba-mazepine or TCAs Neurogenic pain (continuous and touch-evoked); nociceptive pain Moderate/severe neurogenic pain; allodynia, tolerance not developed Nociceptive and neurogenic pain when other agents have failed A Clinical Bulletin from the Professional Resource Center of the National Multiple Sclerosis Society Pain is a symptom that demands serious attention, as it has such pervasive impact on role, mood,capacity to work and rest, and interpersonal relationships. Untreated pain causes isolation, anger,and depression. Optimum therapeutic treatment involves a commitment to the goal of controllingpain and improving quality of life.
REFERENCES
1. Pollmann W, Feneberg W, Erasmus LP. Pain in multiple sclerosis—A still underestimated problem. The 1 year prevalence of pain syndromes, significance and quality of care of multiplesclerosis inpatients. Nervenarzt 2004; 75(2): 135–140.
2. Solaro C, Brichetto C, Amato MP, Colombo C, D’Aleo G, Gasperini C, et al. PaIMS study group.
The prevalence of pain in multiple sclerosis: A multicenter cross-sectional study. Neurology2004; 63(5): 919–921.
3. Ehde D, Gibbons L, Chwastiak L, Bombardier C, Sullivan M, Kraft G. Chronic pain in a large community sample of persons with multiple sclerosis. Multiple Sclerosis 2003; 9(6): 605–611.
4. Svendsen K, Jensen T, Overvad K, Hansen H, Koch-Henriksen N, Bach F. Pain in patients with multiple sclerosis: A population-based study. Archives of Neurology 2003; 60(8): 1089–1094.
5. Brichetto G, Messmer-Uccelli M, Mancardi G, Solaro C. Symptomatic medication use in multiple sclerosis. Multiple Sclerosis 2003; 9(5): 45–60.
6. McCaffery M. Two myths about pain. Nursing Life 2006; 4(2): 30.
7. Moulin D, Foley K, Ebers G. Pain syndromes in multiple sclerosis. Neurology 1988; 38: 8. Kalia L, O’Connor P. Severity of chronic pain and its relationship to quality of life in multiple sclerosis. Multiple Sclerosis 2005; 11(3): 322–327.
9. Osterberg A, Boivie J, Thuomas KA. Central pain in multiple sclerosis—Prevalence and clinical characteristics. European Journal of Pain 2005; 9(5): 531–542.
10. Ehde D, Osborne T, Jensen M. Chronic pain in persons with multiple sclerosis. Physical Medical Rehabilitation Clinics of North America 2005; 16(2): 503–512.
11. Rae-Grant AD, Eckert NJ, Bartz S, Reed JF. Sensory symptoms of multiple sclerosis: A hidden reservoir of morbidity. Multiple Sclerosis 1999; 5(3): 179–184.
12. Hansson PT, Fields HL, Hill RG, Marchettini P (eds.). Progress in pain research and management (Vol. 21). Neuropathic pain: Pathophysiology and treatment. Seattle, WA: IASP Press, 2001.
13. D’Aleo G, Sessa E, D’Aleo P, Rifici C, Di Bella P, Petix M, Bramanti P. Nociceptive R3 reflex in relapsing-remitting multiple sclerosis patients. Functional Neurology 1999; 14(1): 43–47.
14. Spissu A, Cannas A, Ferrigno P, Pelaghi AE, Spissu M. Anatomic correlates of painful tonic spasms in multiple sclerosis. Movement Disorders 1999; 14(2): 331–335.
A Clinical Bulletin from the Professional Resource Center of the National Multiple Sclerosis Society 15. Merskey H, Bogduk N. International association for the study of pain. Task force on taxonomy. Classification of chronic pain (2nd ed.). Seattle, WA: IASP Press, 1994.
16. Woolf C, Mannion R. Neuropathic pain: Etiology, symptoms mechanisms and management.
Lancet 1999: 353:1959–1969.
17. Hooge J, Redekop W. Trigeminal neuralgia in multiple sclerosis. Neurology 1999; 45: 18. Kaufmann A, Patel M. (2001). Surgical treatment of trigeminal neuralgia. Retrieved on January 3, 2006, from http://www.umanitoba.ca/centres/cranial.nerves/trigeminal_neuralgia/manuscript/index.html.
19. De Simone R, Marano E, Brescia Morra V, Ranieri A, Ripa P, Esposito M, et al. A clinical comparison of trigeminal neuralgic pain in patients with and without underlying multiplesclerosis. Neurological Science 2005; 26(Suppl. 2): s150–s151.
20. Olafson R, Rushton J, Sayre G. Trigeminal neuralgia in a patient with multiple sclerosis: An autopsy report. Journal of Neurosurgery 1966; 24: 755–759.
21. Chong MS, Bajwa Z. Diagnosis and treatment of neuropathic pain. Journal of Pain and Symptom Management 2003; 25(5 Suppl.): S4–S11.
22. Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, et al. Advances in neuropathic pain: Diagnosis, mechanisms, and treatment recommendations. Archives of Neurology2003; 60(11): 1523–1534.
23. Kondziolka D, Lunsford LD. Percutaneous retrogasserian glycerol rhizotomy for trigeminal neuralgia: Technique and expectations. Neurosurgical Focus 2005; 18(5): E7.
24. Pickett G, Bisnaire D, Ferguson G. Percutaneous retrogasserian glycerol rhizotomy in the treatment of tic douloureux associated with multiple sclerosis. Neurosurgery 2005; 56(3):537–545.
25. Berk C, Constantoyannis C, Honey C. The treatment of trigeminal neuralgia in patients with multiple sclerosis using percutaneous radiofrequency rhizotomy. Canadian Journal of NeurologicalScience 2003; 30(3): 220–223.
26. D’Amico D, La Mantia L, Rigaminti A, Usai S, Mascoli N, Milanese C, et al. Prevalence of primary headache in people with multiple sclerosis. Cephalalgia 2004; 24(11): 980–984.
27. Gee J, Chang J, Dublin A,Vijayan N. The association of brainstem lesions with migraine-like headache: An imaging study of multiple sclerosis. Headache 2005; 45(6): 670–677.
28. Sandyk R, Awerbuch G. The co-occurrence of multiple sclerosis and migraine headache: The serotoninergic link. International Journal of Neuroscience 1994; 76(3–4): 249–257.
29. Belgrade M. Following the clues to neuropathic pain: Distribution and other leads reveal the cause and the treatment approach. Postgraduate Medicine 1999; 106(6): 127–132, 135–140.
A Clinical Bulletin from the Professional Resource Center of the National Multiple Sclerosis Society 30. Gilroni, M. Combination pharmacotherapy for neuropathic pain: Current evidence and future directions. Expert Review of Neurotherapeutics 2005; 5(6): 823–830.
31. Beydoun, A. Neuropathic pain: From mechanism to treatment strategies. Journal of Pain Symptom Management 2003; 25(Suppl. 5): S1–S3.
32. National Pharmaceutical Council (NPC) & Joint Commission on Accreditation of Healthcare Organizations (JCAHO). (2001). Pain: Current understanding of assessment, management,and treatments. [Monograph] Retrieved on January 3, 2006, from http://www.jcaho.org/news+room/health+care+issues/pain_mono_npc.pdf 33. Department of Health and Human Services (DHHS), U.S. Food and Drug Administration, Center for Drug Evaluation and Research. (July 18, 2005). COX-2 selective (includes Bextra,Celebrex, and Vioxx) and non-selective non-steroidal anti-inflammatory drugs (NSAIDs).
Retrieved on November 29, 2005, from http://www.fda.gov/cder/drug/infopage/cox2/ 34. Kalman S, Osterberg A, Sorenson J, Boivie J, Bertler A. Morphine responsiveness in a group of well-defined multiple sclerosis patients: A study with i.v. morphine. European Journal of Pain2002; 6(1): 69–80.
35. Eisenberg E, McNicol E, Carr D. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin. Systemic review and meta-analysis of randomizedcontrolled trials. Journal of the American Medical Association 2005; 293: 3042–3052.
36. Rowbotham MC, Twilling L, Davies PS, et al. Oral opioid therapy for chronic peripheral and central neuropathic pain. New England Journal of Medicine 2003; 348: 1223–1232.
37. Guarino A, Cornell M. Opioids as a treatment option for MS patients with chronic pain.
International Journal of MS Care 2006; 7(1): 10–15.
38. Rog D, Nurmikko T, Friede T, Young C. Randomized controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005; 65(6): 812–819.
39. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomized double blind placebo controlled crossover trial. British MedicalJournal 2004; 329: 353–358.
40. Smith, PE. The safety of cannabinoids for the treatment of multiple sclerosis. Expert Opinion Drug Safety 2005; 4(3): 443–446.
41. Eldridge PR, Sinha AK, Javadpour M, Littlechild P, Varma TR. Microvascular decompression for trigeminal neuralgia in patients with multiple sclerosis. Stereotactic Functional Neurosurgery2003; 81(1–4): 57–64.
This publication is supported by an educational grant from Novartis Pharmaceuticals
2006 National Multiple Sclerosis Society

Source: http://biketxq.nationalmssociety.org/docs/HOM/Pain.pdf