Sweatman - Fibromyalgia, Sk M Relaxers, Spasticity

Question 1

Fibromyalgia

Answer 1

• Chronic condition in 2-4% of pop
• Symptoms include: stiffness, tension headache, irritable bowel, difficulty concentrating, mood disorders, restless leg syndrome, urinary complaints
• Exact mech unclear; may be elevated levels of neurotransmitter func in ascending paths of spinal cord and diminished levels in descending -> leads to amplification of nociceptive (pain) signals arriving in brain from peripheral tissues

Question 2

Duloxetine and Milnacipran

Answer 2

• Oral SSRI’s
• MOA: INH reuptake of NE and serotonin (Dulox: ser > NE; Milnac opposite) -> neither has action on receptors themselves, or Dopa receptors; parental agents responsible for pharma effects
• Elim: Dulox -> CYP2D6 (moderate INH) and elim mainly via urinary metabolites; Milnac -> urinary elim of parental drug and metabolites
  1. Neither drug should be given to pts with severe liver dysfunction or alcoholism
• Cautions: both assoc w/mild INC in HR and BP, contra w/uncontrolled closed-angle glaucoma and MAOI’s (temporal spacing needed), may produce hyponatremia (SIADH), and black box warnings for suicidal ideation

Question 3

Pregabalin

Answer 3

• MOA: INH pre-synaptic alpha-2-delta subunits of L-type Ca2+ channels, INH excitatory transmission by glutamate (see attached image)
  1. Seems to alleviate neuropathic pain, anxiety, and pain syndromes
• Elim: rapid absorption and renal elim unchanged w/evidence of renal tubule reabsorption -> dose should be reduced in renal dysfunction/failure
• Cautions: rebound worsening of sxs on drug withdrawal -> may cause dependence w/cont’d use (schedule-V), additive sedation may occur w/other agents that affect CNS in this way, pts should be monitored for worsening depression or suicidal thoughts, dizziness, sedation, blurred vision, and xerostomia may occur (esp. problematic for elderly)
• Monitoring parameters: serum creatinine

Question 4

Amitriptyline and Fluoxetine

Answer 4

• Amitriptyline: TCA
• Fluoxetine (Paxil): SSRI
• Both used “off-label” in tx of fibromyalgia and appear to provide clinical benefit by redressing the imbalance in nuero transmission in ascending vs. descending spinal pain pathways

Question 5

Carisoprodol

Answer 5

• FDA indication for musculoskeletal pain
• MOA: CNS action in reticular activating system and spinal cord, leading to sedation and altered sense of pain -> believed generalized sedation is basis of muscle relaxation (NO direct effect on neuronal conduction, NM transmission, or muscle excitability)
• Elim: CYP2C19 to less active compounds elim’d via urine, renal/hepatic dysfunction INC potential for drug/metabolite retention, INC toxicity
• Cautions: drowsiness and dizziness, CNS things like agitation, insomnia, vertigo, ataxia, asthenia, temp vision loss, mydriasis, ortho hypotension; active sedation if combined w/other sedatives
• Monitoring parameters: serum creatinine/BUN

Question 6

Cyclobenzaprine

Answer 6

• Generic oral drug closely related to Amitriptyline (comparable actions and side effects)
• Not effective for relief of cerebral or spinal cord disease -> indicated for: muscle spasm, fibromyalgia (off-label use)
• MOA: central action, possibly at level of brain stem
• Elim: enterohepatic recirculation and CYP metab (3A4, 1A2, 2D6) w/reduced clearance in elderly and hepatic impairment, anticholinergic effects -> drowsiness, xerostomia, dizziness, fatigue, N/V, constipation, blurred vision (elderly at risk of confusion and CV events leading to falling)
• Cautions: additive CNS depression w/depressant drugs and alcohol, additive effects w/anticholinergic drugs (i.e., atropine, most tricyclics, and 1st-gen anti-histamines), GI problems most significant (e.g., paralytic ileus), have been reported to INC QT interval (careful if pt on antiarrhythmics or o/drugs prolonging QT)

Question 7

Methocarbamol

Answer 7

• Oral, IM, or IV -> for: muscle spasm, tetanus
• MOA: no direct effect on muscle or excitation-contraction coupling, effects thought to be due to generalized sedative action, pain relief due to altered pain perception
• Elim: hepatic dealkylation & hydroxylation with urinary elim, significant hepatic/renal dysfunction has potential to INC toxicity
• Cautions: additive CNS depression w/alcohol and o/depressant drugs, common side effects -> N/V, drowsiness, dizziness, lightheadedness, blurred vision, headache, and irritability

Question 8

Tizanidine

Answer 8

• Oral agent that acts as agonist on pre-synaptic alpha-2 receptor, leading to DEC activation of polysynaptic spinal cord motor neurons w/reduction in muscle tone, but not strength (weak, 2-10%, anti-hypertensive activity, unlike Clonidine)
• Indications: MS, spasticity, and spinal cord trauma
• Elim: first-pass metab, short half-life w/renal elim of long-lasting metabs, clearance w/reduced w/renal dysfunc (CrCl < 25 mL/min) and advancing age -> dose should be titrated up to effect to avoid excessive toxicity
• Cautions: hepatocellular toxicity, tapered cessation to avoid rebound hypertonicity, tachycardia, and HTN, esp after high drug doses, additive CNS depression w/CNS depressants, additive hypo-tension w/clonidine, methyldopa, guanfacine, or guanabenz, common side effects -> asthenia, xerostomia, dizziness, sedation, hypotension
• Monitoring parameters: LFT’s

Question 9

Why aren’t Baclofen and Dantrolene commonly used as muscle relaxers?

Answer 9

• Because they produce muscle relaxation at doses that produce significant sedation
• They all act in the spinal cord (see attached image)

Question 10

Baclofen

Answer 10

• MOA: GABA_B agonist at multiple levels in spinal cord, producing INH signals or hyperpolarizing, DEC excitatory (aspartate, glutamate) polysynaptic paths
  1. Pain relief via INH of substance P action
  2. Sedation at high doses; some supraspinal action
  3. Indications: MS, muscle spasm, spasticity, spinal cord trauma
• Elim: orally active, renal elim, renal dysfunc/failure can lead to encephalopathy, abdominal pain, seizures, and respiratory depression
• Cautions: black box warning for abrupt discontinuance b/c rebound neural activity can cause seizures, confusion, hallucinations, psych disturbances (esp. if preexisting CNS condition), and INC spasticity (rhabdomyolisis, multisystem failure, death) -> tapered dosing over 2 or more wks
  1. Additive CNS depression w/o/depressants
  2. Additive hypotension w/anti-HTN, MAOI’s
  3. Dose adjustment of anti-diabetic agents maybe b/c INC blood glucose
  4. Common: drowsiness, asthenia, confusion, fatigue, headache (rarely observe o/CNS tox., except w/renal failure or abrupt withdrawal)

Question 11

Dantrolene

Answer 11

• MOA: DEC muscle contraction by interfering w/Ca release (via ryanodine receptor) from sarcoplasmic reticulum -> uncouples excitation-conduction process (useful in treating malignant hyperthermia)
  1. Little or no effect on cardiac or sm m at doses used for sk m relaxation
  2. Indications: malignant hyperthermia, MS, neuroleptic malignant syndrome, spasticity
• Dosing: oral or IV (solubilized w/surfactant + water b/c very alkaline and produces thrombophlebitis; admin into fast-running infusion or lg vein, and need for reconstitution delays admin)
• Elim: hepatic metab, inactive metabs renally elim, package notes assoc w/hepatotox, esp. in F > 35, pts w/MS, and concurrent drug tx (esp. estrogens); crosses placenta, and can produce floppy child syndrome (hypotonia) if used during C-section
• Cautions: additive CNS depression w/o/CNS depressants, IV Dantro combined w/CCB’s (in tx of malignany hyperthermia) may produce Vfib and CV collapse; common side effects -> muscle weakness leading to drooling, dysarthria (difficulty speaking), enuresis, myalgias (involuntary urination), backache
• Monitoring parameters: LFT’s

Question 12

Botulinum toxin

Answer 12

• All serotypes interfere w/neural transmission by blocking release of Ach, causing muscle paralysis
• Weakness induced by injection usually lasts about three months
• Now plays a significant role in the mgmt of a wide variety of med conditions, esp strabismus and focal dystonias, hemifacial spasm, and various spastic mvmt disorders, headaches, hypersalivation, hyperhidrosis, and some chronic conditions that respond only partially to medical treatment
• This is what Google says…