Chronic Pain in Neuromuscular Disease Gregory T. Carter, MD, MS
Disclosure
Nothing to Disclose
Learning Objectives Describe the nature and scope of pain in neuromuscular disorders Recognize the major components of disease burden with respect to pain in neuromuscular disorders List effective drug treatments for chronic pain in neuromuscular disorders
Major Neuromuscular Disorders (NMDs) Duchenne/Becker muscular dystrophy: DMD/BMD Myotonic muscular dystrophy, types 1 & 2 (MMD) Limb Girdle muscular dystrophy (LGMD) Facioscapulohumeral (FSHD) Charcot Marie Tooth disease (CMT) Spinal Muscular Atrophy (SMA) Amyotrophic Lateral Sclerosis (ALS)
Major Neuromuscular Disorders [NMDs] (cont’d)
Guillain Barre – acute and chronic inflammatory demyelinating polyneuropathy (AIDP/CIDP) Myasthenia gravis (MG) Inclusion body myositis (IBM) Polymyositis/Dermatomyositis Post Polio Syndrome (PPS)
Major Neuromuscular Disorders [NMDs] (cont’d) Pain is a common problem in NMD There are important differences between different NMD groups on the nature and scope of pain and its impact More research is needed Need more effective treatments for NMD-related pain
Chronic pain in persons with neuromuscular disease. Arch Phys Med Rehabil 2005;86:1155-63.
Factors that impact Pain in NMD Distribution of weakness Severity of weakness The relative suddenness of loss Presence of sensory impairment Presence of cognitive effects Speech and swallowing Labored or restricted breathing
Shoulder pain
Neck Pain, Visual Problems
Patient Care Team NMDS: Not Curable but Teatable Physician (neurology/physiatry) Coordinates Overall Care Paln
Physical/Occupational Therapists Speech Language Pathologist
Clinical Nurse Specialist Social Worker Psychologist MDA PSC
Consulting Physicians Pulmonologist Orthopedic Surgery GI Surgery
Types of Pain Muscular/cramping Neuropathic Musculoskeletal Psychological
Exercise Induced Muscle Injury Constant low level exercise in dystrophic mouse muscle induces significant damage histologic observation shows necrosis Fluorescent dextrans are seen with myofibers There is significant decrease in tetanic and twitch tension/contraction time There is preferential damage to slow oxidative fibers with concentric injury. In contrast, fast glycolytic muscles are more impaired by eccentric contractions Muscle Nerve 1997; 20(3):393-395 Neuromusc Disord 1995; 5(4):323-331 Arch Phys Med Rehabil 1994; 75(5):555-559
Other Possible Mechanisms of Muscle Cramping and Pain Impaired cell membrane signaling Increased oxidative stress (secondary to lipid peroxidation, entry of Ca++, leading to cell death) Muscle ischemia (due to interruption of microvasculature)
Proposed Mechanisms for Myofiber Cramping and Pain SG - YES LEAKY Membrane
Dystrophin Absence
1B Sarcoglycan Deficiency Muscle Ischemia Ischemic Pain
Sarcolemmal Instability
γSG - NO others - ?
Mechanical Weakening of Sarcolemma
Membrane Lesions
Calcium Influx
Oxidative Stress
APOPTOSIS / NECROSIS
Cramping and pain
Am J Phys Med Rehabil 2002;(81):151-161
Neuropathic Pain Of 617 CMT subjects, 440 (71%) reported pain Most severe neuropathic pain sites were ankles (50%), toes (46%), and feet (44%) 171 (39%) reported interruption of ADLs by pain 168 (38%) used non-narcotic pain meds 113 (23%) used narcotics for pain Descriptors for CMT were similar to PHN, CRPS-1, DN, and PNI in terms of intensity and the descriptors hot, dull, and deep Arch Phys Med Rehabil 1998; 79:1560-4
Musculoskeletal Pain We examined health-related QoL and pain in NMD using SF-36 Assesses pain severity using Bodily Pain scale 1,432 participants normed with nondisabled adults Am J Hosp Palliat Care 2002;19(1):39-48.
Musculoskeletal Pain Frequency and severity of musculoskeletal type pain reported in NMD was significantly greater than levels of pain reported by the general United States population and was comparable to pain reported by subjects with osteoarthritis and chronic low back pain
Am J Hosp Palliat Care 2002;19(1):39-48.
Psychological Pain In NMD, like the general population, there is a significant correlation between pain and depression. This creates fatigue, sleep disturbance, loss of vitality, and decreased social interactions
Am J Hosp Palliat Care 2002;19(1):39-48.
Management Approach Treat the whole patient, not just a diagnosis or symptom Manage symptoms aggressively and completely: take a “24/7/365” viewpoint right from the beginning Multidisciplinary management should ALWAYS be considered Educate your patient right from the start
Multidisciplinary Management Physician Nurse Physical Therapists Occupational Therapists Respiratory therapist Social worker Dietician
Symptom Management Pain – often related to immobility Muscle spasms and weakness Fatigue Dyspnea/Shortness of breath Dysphagia/Secretion control Depression
Initial Evaluation Define physical limitations (impairment) Define physical and psychological barriers (disability) Identify societal integration barriers - work, education, etc (handicap) Determine patient goals Orchestrate a rehab program based on their goals and expectations
The Role of Exercise in Treating Pain Growing body of evidence that exercise IS beneficial in treating pain in NMD Submaximal strengthening helps reduce immobility Aerobic conditioning Stretching Pool therapy is ideal as the heat of the water helps with pain; also helps with spasticity
Exercise Precautions in NMD Aggressive (maximal) strengthening program may be deleterious and increase pain Watch for signs of overwork weakness Hydration Nutrition Warm up/cool down Rest days
Physical Therapy Modalities for Pain in NMD Ultrasound 102 watts/cm2 over painful joints – works very well in shoulders for adhesive capsulitis Iontophoresis with dexamethasone Myofascial release massage – better tolerated than deep tissue Heat/ice
Bracing (Orthotics) to Limit Pain
Goals –stabilize joint – reduce joint damage –provide support –improve function –prevent further injury from hypermobility
Ankle Foot Orthoses (AFOs) What works best? –polypropylene or carbon fiber –non-articulated –adjust as needed – high v. low profile –partial foot lever
Walking Aids Single point cane – aids balance only Quad cane – balance and some fall protection Walker – good fall protection; need arm strength Canes need to be fit properly – if too long or too short they may INCREASE fall risk! Adjustable aluminum canes are easiest to use and lightest – fancy wooden canes are not often the best choice: heavier, not adjustable
Upper Extremity Bracing Degree of weakness and deformity important in determining utility of bracing Make sure the brace IMPROVES function (this is trickier in the upper extremities!) as well as reduces pain Custom made splints are usually necessary
Medications to Managing pain in NMD Must address spasticity as well Depression may be complicating treatment May sometimes see neuropathic pain in NMD: hyperpathia, allodynia Dysautonomia with hyperhidrosis – may be unpleasant
Characteristics of Pain in NMD Mostly Mechanical: dull, aching pain due to immobility and spasticity Neuropathic pain: paroxysmal, sharp, stabbing, shooting pain (hyperalgesia, allodynia)
Tri-Cyclic Antidepressants in Neuropathic Pain Study
n
Response
Watson, et al (1982)
24
A: 67%
P: 5%
24
A: 47%
P: 8%
19
D: 63%
P: 11%
32
A: 44%
M: 18%
15
A: 60%
Z: 7%
Amitriptyline vs placebo
Max, et al (1988) Amitriptyline vs placebo
Kishore-Kumar et al (1980) Desipramine vs placebo
Watson, et al (1992) Amitriptyline vs maprotiline
Watson and Evans (1985) Amitriptyline vs zimeldine [SSRI]
Max MB. Ann Neurol. 1994;35(suppl):S50–S53.
Anti-Depressants and Pain Older anti-depressants better studied –Newer agents have less side effects, thus have better compliance –Newer agents appear just as effective for pain
Duloxetine 60 mg PO daily (FDA approved for Fibromyalgia) Venlafaxine extended release 150 mg PO Daily If sexual side effects add bupropion 75 mg PO daily
Tricyclic Antidepressants and Neuropathic Pain Good if sleep disturbance present Start low and go slow.
Dose range between 50-150 mg/day for nortriptyline Monitor side effects: dry mouth, weight gain, cardiac May cause hang over if taken too late Amitriptyline may cause WEIGHT GAIN
Antiepileptic Drugs Antiepileptic drugs are very effective for neuropathic pain but also work in myalgias/myofascial pain seen in myositis Pregabalin or Gabapentin are preferred choices Minimal side effects, high dose ceiling
Muscle Relaxers? Very sedating Do not actually “relax” muscle Cyclobenzaprine initially marketed as an antidepressant Carisoprodol is a BAD ACTOR: metabolized in to meprobamate
FINALLY OPIOIDS: Pros/Cons/Risks/Benefits
Good analgesia vs dependence High dosing ceiling vs toxicity Risk for addiction Drug-drug interactions Watch for respiratory suppression and constipation
New Trend/OLD medicine: Cannabis Emerging evidence that they are effective in the Management of NMD Pain Neuropathic and myofascial pain May help with spasticity too NMD model animal studies show cannabinoids are neuroprotective
Nomenclature  The terms cannabis and marijuana (also spelled "marihuana") will be used interchangeably to refer to any preparation of the cannabis plant intended for medicinal purposes (cannabinoid botanicals). The preferred term is medicinal cannabis  There are at least three species of the cannabis genus, those being cannabis sativa, cannabis indica, and cannabis ruderalis, any of which may be used for medicinal purposes
Cannabis One of the oldest known psychoactive plants - first documented use as medicine > 5000 years ago in China There are 3,000-year-old Egyptian mummies that contain cannabis traces (still active!) Introduced into Western medicine in 1840’s by Dr. W.B. O’Shaughnessy One of earliest cultivated non-food plants: – fiber for rope, seeds for oil and birdseed – mixture of leaves, stems, tops
Circa 1900… Many cannabis based medications were produced commercially Eli Lilly, Parke-Davis, and Sharp Dohme (now Merck Sharp Dohme) Tinctures; Pills; Liniments Sometimes mixed with other compounds
Cannabis Tincture, circa 1910, Parke Davis
Cannabis for Neuropathic Pain 1906
Cannabis for Neuralgia 1925
The Chemical Makeup of Cannabis The active ingredients in cannabis are cannabinoids, a group of terpenophenolic compounds The cannabinoids are concentrated in a viscous resin that is produced in glandular structures known as trichomes These are the tiny, sticky hair like formations you see at the end of buds
Uses in NMD Analgesia Anti- inflammatory Antispasmodic/anticonvulsant Enhance appetite Improved tolerability and efficacy of opioids No constipation or respiratory suppression No LD50
Major Cannabinoids Found in Cannabis and Putative Effects Delta-9-tetrahydrocannabinol (THC): most psychoactive, lesser therapeutic Cannabidiol (CBD): analgesia; moderates effects of THC Cannabinol (CBN): anticonvulsant Tetrahydrocannabivarin (THCV): anti-inflammatory Cannabichromene (CBC): mixed effects Cannabicyclol (CBL): analgesic Plus 80-100 other cannabinoids
Clinical Pharmacology Of Cannabis 95-99% plasma protein bound; lipophilic hydroxylation, oxidation, and conjugation for rapidly clearance from plasma First-pass metabolism (after PO admin) to 11-OH-THC Elimination is slow: days to weeks 20-35% found in urine; 65-80% found in feces; stored in adipose; Pregnancy Category C: in breast milk Fast, good absorption if smoked or vaporized (20-37%) Slower if orally ingested; Local effects if liniment
The Endocannabinoid System Endocannabinoid system is intricately involved in normal human physiology, specifically in the control of movement, pain, memory, mood, motor tone, and appetite, among others Cannabinoid receptors are found in the brain and peripheral tissues Dense receptor concentration in the cerebellum, basal ganglia, and hippocampus Few cannabinoid receptors in the respiratory areas in brainstem
Cannabinoid Receptors
G-protein-coupled receptors CB1 receptors highly expressed in the brain
– CB1 receptors also found in adipose tissue, liver, muscle, the gastrointestinal tract, pancreas, as well as reproductive and cardiovascular tissues
CB2 receptors are expressed primarily in immune cells – CB2 receptor expression in neurons is being studied
Devane WA et al. Mol Pharamcol. 1988;34:605-613. Munro S et al. Nature. 1993;365:61-65. Ameri A. Prog Neurbiol. 1999;68:315-348. Osei-Hyiaman D, DePtrillo M, Pacher P, et al. J Clin Invest 2005;115:1298-1305. Cota D, Woods SC. Curr Opin Endocrinol Diabetes. 2005;12338-351.
Key ECS Elements Cannabinoid Receptors Are G-Protein-coupled Receptors
CB1 receptor
AEA also an endovanalloid at TRPV1 (with 520-fold lower affinity cf with CB1); also PPARy
Endocannabinoids
CB2 receptor Endogenous, phospholipid-derived metabolites that bind to and activate cannabinoid receptors De Petrocellis et al. Br J Pharmacol. 2004:141:765-774 Pertwee et al. Pharmacol Ther. 1997:74:129-180 Roche R et al. Histochem Cell Biol. 2006;126(2): 177-187
The CB1 Receptor Activation negatively coupled to adenylate cyclase, suppresses neuronal Ca2+ conductance, inhibits inward rectifying K+ conductance suppression of neuronal excitability CB1 receptor consists of 7 transmembrane helices Courtesy of Patricia Reggio, PhD
Difference Between Classical and Retrograde Neurotransmission Presynaptic
Postsynaptic
Classical Neurotransmitter
Retrograde Neurotransmitter
Presynaptic
Postsynaptic Di Marzo V, Matias I. Nat Neurosci. 2005;8:585-589. Di Marzo Vet al. Nat Rev Drug Discover. 2004:3:771-784. Wilson RI, Nicoll RA. Nature. 2001;410:588-592. Vaughan CW, Christie MJ. 2005:367-383.
Physiological Effects of Endocannabinoids Endocannabinoids are often produced as an adaptive response to cellular stress, aimed at reestablishing cell homeostasis Endocannabinoids affect a large number of physiologic processes including – Feeding behavior – Energy balance, metabolism, and GI function – Pain perception – Motor control and posture
– Learning, memory and emotions – Immune and inflammatory responses – Cardiovascular function – Reproduction – Bone formation
Cota D, Woods S. Curr Opin Endocrinol Diabetes. 2005;12:338-351; De Procellis L et al. Br J Pharmacol. 2004;141:765-774; Pagotto Uet al. Endocr Rev. 2006;27:73-100; Ameri A. Prog Neurobiol. 1999;58:315-348; Cota Det al. J Clin Invest. 2003;112:423-431; Di Marzo V, Matias I. Nat Neurosci. 2005;8:585-589; Kershaw EE, Flier JS. J Clin Endocrinol Metab. 2004;89:2548-2556; Correa F et al. Mini Rev Med Chem. 2005;5:671-675; van der Stelt M et al. Embo J 2005;24:3026-3037; Wang H et al. Endrocr Rev. 2006;27:427-448; Idris Al et al. Nat Med. 2005;11:774-779; de Oliveira Alvares L et al. Brain Res. 2006;1075:60-67; Arenos JD et al. Eur J Pharmacol. 2006;539:177-183; Mikics E et al. Behav Pharmacol. 2006;17:223-230; Guindon J et al. Pain. 2006: 121:85-93.
Cannabinoids Suppressed Neuropathic Pain in 9 Animal Models Chronic constriction injury: infraorbital nerve, saphenous nerve Partial nerve ligation: sciatic, saphenous Spinal nerve ligation: L5 Spared nerve injury Spinal cord injury Tibial nerve injury Streptozotocin-induced diabetic neuropathy Rahn EJ and Hohmann AG. Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside. Neurotherapeutics 2009. 7:4, 713-737
Cannabinoid Suppression of Pain Analgesia: different mechanism than opiates, some synergy though. Spasticity: likely GABA mediated Appetite enhancement: hippocampal? Anti-emetic: cerebellar? Elevated levels of the CB1 receptor are found in areas of the brain that modulate nociceptive processing CB1 and CB2 agonists have peripheral analgesic actions CBs may also exert anti-inflammatory effects Analgesic effects not blocked by opioid antagonists
Abrams DI, Rowbotham MC, Petersen KL, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007; 68(7):515-21
Watch For Side Effects Disinhibition, Sensory - perceptual changes Recent memory impairment Balance/stability impaired Impaired performance on complex motor tasks
Watch for Respiratory Suppression From Narcotics Morning headache, poor sleep: CO2 retention FVC, MIP/MEP, PCF at clinic visits Sublingual or inhaled MS may help actually improve ventilation if used judiciously
Treating Pain by improving mobility Power wheelchair w/Tilt-n-space Hoyer lift Electric hospital bed Pressure relief mattress Assistive devices: raised toilet seat, grab bars, h/h shower PT/OT in home safety eval
Equipment to Help Mobility Braces: AFOs, neck support Canes, walkers Lift chairs Van w/lift Manual wheelchair for back-up
Fatigue in NMD Fatigue is common in many neuromuscular diseases (NMDs), including NMD Fatigue is under-investigated as a clinical problem in NMD and NMD and is often overlooked by clinicians who care for neuromuscular patients.
Fatigue in NMD In patients with NMD, it is unclear if fatigue is an independent symptom that is treatable after treating other symptoms, or simply reflects other easily-measured symptoms such as sleep problems, dyspnea, or depression Fatigue is “multifactorial” in NMD
Fatigue in NMD Research supports aerobic exercise to minimize fatigue [pool may be best] Now good evidence of effectiveness are the use of psychostimulants in selected NMD patients structured energy conservation plan also critical “Pacing”
Fatigue Algorithm
Other Concerns: Pain and Depression, and poor quality of sleep may cause fatigue Impaired pulmonary function Lack of supportive environment for the patient Need to address these issues
Medications for Fatigue in NMD Several medications have been tested in the treatment of fatigue in other diseases: –dopaminergic agent amantadine –amphetamine-related stimulant pemoline –Modafinil, (approved by the FDA for the treatment of narcolepsy) now shown effective for fatigue in NMD in two studies. –Pyridostigmine – only anecdotal evidence
Modafinil Rabkin JG, Gordon PH, McElhiney M, Rabkin R, Chew S, Mitsumoto H – Modafinil treatment of fatigue in patients with ALS: a placebocontrolled study. Muscle Nerve 2009; 39(3):297-303.
32 patients were randomized; 29 completed the 4-week trial. response was 86%, placebo response 14% No serious adverse events
Modafinil  Carter GT, Weiss MD, Lou JS, Jensen MP, Abresch RT, Martin TK, Hecht TW, Han JJ, Weydt P, Kraft GH
15 NMD patients: 2 weeks either 200 mg or 400 mg of modafinil. Side effects were minimal and did not result in any study dropouts. Mean scores on the Fatigue Severity Scale (FSS) decreased from 51.3 (SD 9.2) to 42.8 (SD 10.2). Epworth Sleepiness Scale (ESS), mean scores decreased from 8.2 (SD 2.0) to 4.5 (SD 2.4). Reductions for both scales were significant at p < 0.001. Mean scores on the self-report version of the Functional Independence Measure (FIM-SR) increased from 115.2 (SD 5.6) to 118.1 (SD 5.4), with p < 0.01 Modafinil to treat fatigue in amyotrophic lateral sclerosis: an open label pilot study. Am J Hosp Palliat Care. 2005;22(1):55-9
Maximal Quality of Life (QoL) “An individual’s perception of their position in life in the context of the culture and value systems in which they live, in relation to their goals, expectations, standards, and concerns” WHO, 2001
Comment
ď&#x201A;§These dimensions are NO different for people with neuromuscular disorders or other disabling conditions
Reflections â&#x20AC;&#x153;A wise man should consider that health is the greatest of human blessings. In illness, the body must be treated as a whole and not just a series of partsâ&#x20AC;? Hippocrates
Palliative and Hospice Care in NMD
â&#x20AC;&#x153;He who would teach men to die would at the same time teach them to live" Michel de Montaigne
End of life Planning Have “Do Not resuscitate” order signed and readily available Avoid 911 calls if possible Consult and get in to Hospice program early Plan these things out with family’s input
Ethical Considerations ď&#x201A;§Patients should direct their care. Clinicians provide information and options and be supportive, not directive ď&#x201A;§Dying with any NMD should be peaceful and painfree
Physician Assisted Suicide? Goes against the Oath of Hippocrates Has huge moral and ethical implications If patient requests this, then re-evaluate the care they are getting
Acknowledgements Muscular Dystrophy Association National Institute of Disability and Rehabilitation Research National Institutes of Health