Physical Therapy and Rehabilitation

1. Introduction/Overview

The integration of pharmacological agents within physical therapy and rehabilitation represents a critical therapeutic synergy aimed at optimizing functional recovery and managing the symptom complex associated with musculoskeletal, neurological, and systemic conditions. While physical modalities, exercise, and manual techniques form the cornerstone of rehabilitative medicine, pharmacotherapy serves as a vital adjunct to facilitate participation, manage pain, reduce pathological tone, and control inflammation, thereby enabling more effective therapeutic engagement. This chapter examines the pharmacological principles underlying the drugs most commonly encountered in rehabilitation settings, providing a foundation for rational therapeutic decision-making.

The clinical relevance of this topic is substantial, as effective rehabilitation often hinges on the appropriate management of barriers to participation, such as pain, spasticity, and inflammation. An understanding of the pharmacology of these agents allows clinicians to tailor interventions, anticipate and mitigate adverse effects, and recognize potential drug-drug or drug-therapy interactions. The goal is to employ pharmacotherapy not as a standalone treatment, but as a means to enhance the efficacy of physical and functional retraining.

Learning Objectives

• Classify the major pharmacological agents used as adjuncts in physical therapy and rehabilitation, including analgesics, anti-inflammatory drugs, muscle relaxants, and agents for spasticity management.
• Explain the mechanisms of action, pharmacokinetic profiles, and primary therapeutic applications of these drug classes within a rehabilitative context.
• Analyze the common and serious adverse effects, contraindications, and major drug interactions associated with rehabilitation pharmacology.
• Evaluate special considerations for pharmacotherapy in rehabilitation populations, including pediatric, geriatric, and comorbid patients.
• Integrate pharmacological knowledge with rehabilitative principles to develop strategies for managing pain, spasticity, and inflammation to facilitate functional recovery.

2. Classification

Pharmacological agents used in rehabilitation are classified primarily by their therapeutic intent and mechanism of action. A functional classification is most clinically relevant, as it aligns with the specific barriers to rehabilitation being addressed.

Analgesics

These agents are utilized to manage pain, a ubiquitous impediment to active participation in therapy. They are sub-classified based on their site and mode of action.

• Non-Opioid Analgesics: Acetaminophen (paracetamol).
• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):
  • Non-selective COX inhibitors: Ibuprofen, Naproxen, Diclofenac.
  • COX-2 selective inhibitors: Celecoxib, Etoricoxib.
• Opioid Analgesics:
  • Full agonists: Morphine, Oxycodone, Hydrocodone, Hydromorphone, Fentanyl.
  • Partial agonists/Agonist-antagonists: Buprenorphine, Tramadol (also has SNRI activity).
• Adjuvant Analgesics (for Neuropathic Pain):
  • Anticonvulsants: Gabapentin, Pregabalin, Carbamazepine.
  • Antidepressants: Amitriptyline, Duloxetine, Venlafaxine.
  • Topical agents: Lidocaine patches, Capsaicin cream.

Muscle Relaxants and Spasmolytics

This category targets muscle hypertonia, which can be either spastic (upper motor neuron origin) or non-spastic (musculoskeletal spasm).

• Centrally Acting Skeletal Muscle Relaxants: Baclofen (oral and intrathecal), Tizanidine, Cyclobenzaprine, Methocarbamol, Carisoprodol.
• Peripherally Acting Neuromuscular Blocking Agents: Used in specific settings like surgical procedures or critical care, not typically in ambulatory rehabilitation (e.g., succinylcholine, rocuronium).
• Direct Acting Spasmolytics: Dantrolene (acts directly on skeletal muscle).
• Neurotoxins: Botulinum toxin serotypes A and B (chemodenervation).

Anti-Inflammatory Agents

• Glucocorticoids (Corticosteroids): Prednisone, Methylprednisolone, Triamcinolone, Dexamethasone. Used systemically or via local injection.
• NSAIDs: As listed under analgesics, due to their dual analgesic and anti-inflammatory properties.
• Disease-Modifying Antirheumatic Drugs (DMARDs): Methotrexate, Sulfasalazine, Leflunomide. Used in chronic inflammatory conditions like rheumatoid arthritis.
• Biologic Response Modifiers: TNF-α inhibitors (e.g., adalimumab, etanercept), IL-1 and IL-6 inhibitors.

Other Adjunctive Agents

• Osteoporosis Management: Bisphosphonates (alendronate, zoledronic acid), Denosumab, Teriparatide.
• Cartilage and Joint Health: Symptomatic slow-acting drugs for osteoarthritis (SYSADOA) such as glucosamine, chondroitin (evidence is equivocal).
• Central Nervous System Stimulants: Used in specific contexts like post-stroke fatigue or traumatic brain injury (e.g., methylphenidate, modafinil).

3. Mechanism of Action

Analgesics

Non-Opioid Analgesics: The precise mechanism of acetaminophen remains incompletely understood but is thought to involve central inhibition of prostaglandin synthesis, possibly through a cyclooxygenase (COX) isoenzyme variant (COX-3), and modulation of descending serotonergic pathways.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): These agents exert their effects primarily through the reversible (non-selective) or preferential/selective (COX-2 inhibitors) inhibition of the cyclooxygenase enzymes, COX-1 and COX-2. COX enzymes catalyze the conversion of arachidonic acid to prostaglandin H2, a precursor for various prostanoids including prostaglandin E2 (PGE2) and prostacyclin (PGI2). PGE2 is a key mediator of pain sensitization (hyperalgesia) and inflammation at peripheral sites. By reducing prostaglandin synthesis, NSAIDs decrease inflammation, pain, and fever. COX-1 inhibition is also responsible for gastrointestinal and renal adverse effects due to the loss of cytoprotective prostaglandins.

Opioid Analgesics: Opioids act as agonists at endogenous opioid receptors (mu-δ-κ- and nociceptin/orphanin FQ receptors) distributed throughout the central and peripheral nervous systems. The primary analgesic effect is mediated through mu-opioid receptor (MOR) activation in the brainstem, thalamus, and spinal cord dorsal horn. Activation inhibits the release of excitatory neurotransmitters (e.g., substance P) from primary afferent neurons and hyperpolarizes postsynaptic neurons, thereby reducing nociceptive transmission. Supraspinal activation also modulates the affective component of pain.

Adjuvant Analgesics:

• Gabapentin and Pregabalin: These alpha-2-delta ligands bind to the α2δ subunit of voltage-gated calcium channels on presynaptic neurons in the spinal cord and brain. This binding reduces the influx of calcium, which subsequently diminishes the release of excitatory neurotransmitters such as glutamate, norepinephrine, and substance P, thereby attenuating central sensitization and neuropathic pain.
• Tricyclic Antidepressants (e.g., Amitriptyline): Analgesia is primarily attributed to the inhibition of serotonin and norepinephrine reuptake in descending inhibitory pain pathways in the central nervous system, enhancing endogenous pain modulation. Their anticholinergic and sodium channel blocking properties may also contribute.
• Serotonin-Norepinephrine Reuptake Inhibitors (e.g., Duloxetine): Mechanism is similar to TCAs but with greater selectivity for monoamine reuptake inhibition and a more favorable side effect profile.

Muscle Relaxants and Spasmolytics

Baclofen: A gamma-aminobutyric acid (GABA) analogue that acts as a selective agonist at GABA_B receptors. In the spinal cord, activation of presynaptic GABA_B receptors inhibits the release of excitatory neurotransmitters (e.g., glutamate, aspartate) from primary afferent terminals. Postsynaptic receptor activation increases potassium conductance, leading to membrane hyperpolarization and reduced excitability of motor neurons. The net effect is the suppression of monosynaptic and polysynaptic spinal reflexes, reducing spasticity.

Tizanidine: An imidazoline derivative and central alpha-2 adrenergic receptor agonist. Its anti-spastic effect is mediated primarily at the spinal cord level, where it enhances presynaptic inhibition of motor neurons, likely by increasing the release of glycine, an inhibitory neurotransmitter. It may also have effects at supraspinal sites.

Dantrolene: Unlike centrally acting agents, dantrolene sodium acts directly on skeletal muscle. It inhibits the release of calcium ions from the sarcoplasmic reticulum into the myoplasm by antagonizing ryanodine receptors (RyR1). This uncouples excitation-contraction coupling, reducing muscle contraction force without affecting neuronal conduction or neuromuscular junction transmission. It is particularly effective against spasticity of peripheral origin.

Botulinum Toxins: These neurotoxins act at the neuromuscular junction. They are internalized by the presynaptic nerve terminal and cleave specific proteins involved in the docking and fusion of acetylcholine-containing vesicles with the presynaptic membrane. Botulinum toxin A cleaves SNAP-25, while toxin B cleaves VAMP/synaptobrevin. This proteolytic action inhibits the exocytotic release of acetylcholine, resulting in a temporary, dose-dependent chemical denervation and muscle relaxation.

Anti-Inflammatory Agents

Glucocorticoids: These lipophilic hormones diffuse across cell membranes and bind to cytosolic glucocorticoid receptors. The ligand-receptor complex translocates to the nucleus, where it modulates gene transcription. It can increase the transcription of anti-inflammatory proteins (e.g., lipocortin-1, IL-10) and, more importantly, repress the transcription of genes coding for pro-inflammatory mediators such as cytokines (IL-1, IL-2, IL-6, TNF-α), chemokines, adhesion molecules, and enzymes like COX-2 and inducible nitric oxide synthase (iNOS). This results in broad suppression of inflammation, immune cell function, and capillary permeability.

Disease-Modifying Antirheumatic Drugs (DMARDs): Mechanisms vary. Methotrexate, a folate antagonist, is thought to exert anti-inflammatory effects at low doses by increasing extracellular adenosine, a potent anti-inflammatory autocoid that inhibits neutrophil adhesion and oxygen radical generation, and decreases cytokine production. Sulfasalazine is metabolized to 5-aminosalicylic acid and sulfapyridine, with effects that may include inhibition of NF-κB and cytokine production.

Biologic Agents: These are monoclonal antibodies or receptor fusion proteins that target specific components of the immune system. For example, TNF-α inhibitors (adalimumab, etanercept, infliximab) bind to and neutralize soluble and membrane-bound TNF-α, a pivotal cytokine in the inflammatory cascade of diseases like rheumatoid arthritis and spondyloarthritis, thereby reducing synovial inflammation and joint destruction.

4. Pharmacokinetics

Pharmacokinetic parameters significantly influence dosing schedules, onset of action, and the potential for drug accumulation, especially in rehabilitation populations who may have age-related or disease-related alterations in organ function.

Analgesics

Acetaminophen: It is rapidly and almost completely absorbed from the GI tract, with peak plasma concentration (C_max) occurring within 30-60 minutes. It is uniformly distributed throughout most body fluids. Metabolism occurs primarily in the liver via glucuronidation and sulfation pathways, with a small fraction (≈5-10%) oxidized by cytochrome P450 enzymes (mainly CYP2E1) to a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is normally detoxified by glutathione. The plasma half-life (t_1/2) is approximately 2-3 hours in adults but can be prolonged in hepatic impairment.

NSAIDs: Most are well absorbed orally, often with high bioavailability (>80%). They are highly protein-bound (>95%), primarily to albumin. This high protein binding is a source of significant drug interactions. Metabolism occurs mainly in the liver via cytochrome P450 pathways (e.g., CYP2C9 for ibuprofen, celecoxib) and glucuronidation. Renal excretion of unchanged drug or metabolites is the primary route of elimination. Half-lives vary widely, from short (ibuprofen, t_1/2 ≈ 2 hrs) to long (piroxicam, t_1/2 ≈ 50 hrs; celecoxib, t_1/2 ≈ 11 hrs), influencing dosing frequency.

Opioids: Oral bioavailability varies significantly due to first-pass metabolism. For example, morphine has low oral bioavailability (≈25%), while oxycodone has higher bioavailability (≈60-85%). They are distributed widely, with lipophilic opioids like fentanyl having a large volume of distribution. Metabolism is primarily hepatic: morphine undergoes glucuronidation to active (morphine-6-glucuronide) and inactive metabolites; oxycodone is metabolized by CYP3A4 and CYP2D6; hydrocodone by CYP2D6 to hydromorphone. Renal excretion is key, and accumulation of active metabolites in renal failure can cause toxicity.

Gabapentin and Pregabalin: Gabapentin exhibits dose-dependent, saturable absorption via the L-amino acid transporter in the small intestine, leading to unpredictable bioavailability that decreases with increasing dose (from ≈60% at 300 mg to ≈35% at 1600 mg). Pregabalin has linear, dose-proportional absorption with high bioavailability (>90%). Neither drug is metabolized significantly nor protein-bound. They are eliminated unchanged by renal excretion, with half-lives of 5-7 hours (gabapentin) and 6 hours (pregabalin). Dosing must be adjusted for renal function.

Muscle Relaxants and Spasmolytics

Baclofen: Oral baclofen is rapidly absorbed but has poor lipid solubility, limiting its penetration across the blood-brain barrier; hence, high systemic doses are often required for central effect, increasing peripheral side effects. Intrathecal administration delivers the drug directly to the spinal CSF, achieving high concentrations at the site of action with minimal systemic exposure. Oral t_1/2 is 3-4 hours. It is primarily excreted unchanged (70-80%) by the kidneys.

Tizanidine: It is well absorbed orally but undergoes extensive first-pass metabolism, resulting in a bioavailability of about 40%. It is metabolized primarily by CYP1A2 in the liver to inactive metabolites. Its half-life is short, approximately 2-4 hours, necessitating multiple daily doses. Food can significantly affect its absorption profile.

Dantrolene: Oral bioavailability is low and variable (≈70% but can range widely). It is metabolized in the liver by microsomal enzymes to 5-hydroxydantrolene, an active metabolite. Both parent and metabolite are excreted in urine and bile. The half-life of the parent compound is approximately 8-9 hours.

Botulinum Toxin: When injected intramuscularly, the large protein molecule (≈150 kDa) acts locally at the neuromuscular junction. Systemic absorption is minimal at therapeutic doses, and systemic effects are rare. The clinical effect begins within 2-3 days, peaks at 2-6 weeks, and gradually wanes over 3-6 months as neuronal sprouting and new neuromuscular junctions form.

5. Therapeutic Uses/Clinical Applications

Analgesics in Rehabilitation

Acetaminophen and NSAIDs: First-line agents for mild to moderate musculoskeletal pain, such as osteoarthritis, acute soft tissue injuries (sprains, strains), and post-operative pain. NSAIDs are preferred when an anti-inflammatory effect is specifically desired, as in tendinitis, bursitis, or rheumatoid arthritis flares. Scheduled dosing, rather than “as-needed,” may be more effective in providing a stable analgesic base to facilitate consistent participation in therapy sessions.

Opioids: Generally reserved for severe acute pain (e.g., post-surgical, major trauma) or moderate to severe chronic pain in carefully selected patients when other therapies are inadequate. In rehabilitation, the goal is often short-term use to overcome a painful initial phase of therapy, with a planned taper as function improves. Long-term use for chronic non-cancer pain is controversial due to risks of tolerance, dependence, opioid-induced hyperalgesia, and adverse effects.

Adjuvant Analgesics: Gabapentin and pregabalin are first-line for neuropathic pain conditions commonly encountered in rehabilitation, including postherpetic neuralgia, diabetic peripheral neuropathy, central neuropathic pain (e.g., post-stroke, spinal cord injury), and radiculopathic pain. Tricyclic antidepressants (e.g., amitriptyline) and SNRIs (duloxetine) are also first-line for neuropathic pain and are particularly useful for comorbid depression or anxiety. Duloxetine is also approved for chronic musculoskeletal pain, including chronic low back pain and osteoarthritis pain.

Muscle Relaxants and Spasmolytics

Centrally Acting Agents (Baclofen, Tizanidine, Cyclobenzaprine): Used to manage spasticity resulting from upper motor neuron lesions (e.g., multiple sclerosis, spinal cord injury, cerebral palsy, stroke). They can reduce clonus, involuntary spasms, and pain associated with spasticity, thereby improving hygiene, positioning, and tolerance for splints or mobility aids. Cyclobenzaprine, methocarbamol, and carisoprodol are more commonly used for short-term relief of acute, painful musculoskeletal conditions associated with muscle spasm, though evidence for superiority over NSAIDs alone is often limited.

Dantrolene: Used for spasticity of cerebral origin (e.g., cerebral palsy, stroke, traumatic brain injury). Because it acts peripherally, it does not cause central nervous system depression but carries a risk of hepatotoxicity and generalized muscle weakness, which can be detrimental to patients with residual functional strength.

Botulinum Toxin: Used for focal spasticity (e.g., upper limb flexor spasticity post-stroke, adductor spasticity in cerebral palsy). It allows for targeted reduction of tone in specific muscle groups, facilitating stretching, orthotic use, and improved function. It is also used for cervical dystonia, spastic bladder, and chronic migraine.

Anti-Inflammatory Agents

Glucocorticoids: Systemic corticosteroids are used in acute exacerbations of autoimmune inflammatory conditions (e.g., rheumatoid arthritis, polymyalgia rheumatica, giant cell arteritis) to rapidly control inflammation and pain. Local injections (intra-articular, peri-tendinous, epidural) are common in rehabilitation for conditions like osteoarthritis of the knee, rotator cuff tendinitis, subacromial bursitis, and radicular pain, providing targeted relief to facilitate physical therapy.

DMARDs and Biologics: These are used for long-term control of chronic inflammatory arthropathies (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis) to prevent joint damage, preserve function, and reduce systemic inflammation. Their use falls under specialist management but is crucial for enabling sustained participation in rehabilitation programs.

6. Adverse Effects

Analgesics

Acetaminophen: At therapeutic doses, it is generally well-tolerated. The principal concern is dose-dependent hepatotoxicity from accumulation of the toxic metabolite NAPQI, which occurs with acute overdose (>10-15 g in adults) or chronic excessive use, particularly in the setting of hepatic impairment, malnutrition, or concomitant use of CYP2E1 inducers (e.g., chronic alcohol use).

NSAIDs: Adverse effects are common and often related to COX-1 inhibition.

• Gastrointestinal: Dyspepsia, gastritis, gastric/duodenal ulceration, bleeding. Risk is increased with age, history of ulcer, concomitant anticoagulants or corticosteroids, and high doses.
• Renal: Reduced renal blood flow (via inhibition of vasodilatory prostaglandins) can cause fluid retention, edema, hypertension, and acute kidney injury, especially in volume-depleted patients or those with pre-existing renal disease.
• Cardiovascular: Non-selective NSAIDs and COX-2 inhibitors may increase the risk of thrombotic events (myocardial infarction, stroke) due to an imbalance between anti-thrombotic prostacyclin (inhibited) and pro-thrombotic thromboxane A2 (less affected by COX-2 inhibitors).
• Other: Platelet dysfunction (reversible with most non-selective NSAIDs except aspirin), bronchospasm in aspirin-exacerbated respiratory disease.

Opioids:

• Common: Constipation (often persistent and requiring proactive management), nausea, vomiting, sedation, dizziness, pruritus, dry mouth.
• Serious: Respiratory depression (the most dangerous acute effect), tolerance, physical dependence, addiction. Opioid-induced hyperalgesia (a paradoxical increase in pain sensitivity) can complicate long-term use. Endocrine effects (hypogonadism) may occur with chronic use.
• Black Box Warnings: For all opioids: risk of addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion by a child; neonatal opioid withdrawal syndrome with prolonged use during pregnancy; and concomitant use with benzodiazepines or other CNS depressants.

Adjuvant Analgesics:

• Gabapentin/Pregabalin: Dizziness, somnolence, peripheral edema, weight gain, blurred vision. Abrupt discontinuation can cause withdrawal symptoms (anxiety, insomnia, nausea).
• Tricyclic Antidepressants: Anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision), orthostatic hypotension, sedation, weight gain, cardiac conduction abnormalities (prolonged QTc interval at higher doses).
• SNRIs (Duloxetine): Nausea (often transient), dry mouth, dizziness, insomnia, increased sweating. May increase blood pressure and heart rate.

Muscle Relaxants and Spasmolytics

Baclofen: Sedation, dizziness, muscle weakness, fatigue, nausea. Abrupt withdrawal, especially of intrathecal therapy, can precipitate a withdrawal syndrome resembling autonomic dysreflexia with hallucinations, seizures, and hyperthermia, which can be life-threatening.

Tizanidine: Sedation, dry mouth, dizziness, hypotension, bradycardia, and hepatotoxicity (elevated liver enzymes in ≈5% of patients, requiring monitoring).

Dantrolene: Dose-dependent muscle weakness, which can limit functional gains. The most serious adverse effect is hepatotoxicity, which can range from asymptomatic elevation of liver enzymes to fatal hepatitis. Risk is higher with doses >400 mg/day, prolonged use, and in females >35 years old. Baseline and periodic liver function monitoring is required.

Botulinum Toxin: Generally well-tolerated. Local effects include injection site pain, bruising, and edema. Unintended weakness of adjacent muscles can occur due to toxin spread. Systemic effects are rare but can include generalized muscle weakness, dysphagia (if neck muscles are injected), and flu-like symptoms. Formation of neutralizing antibodies can lead to treatment failure with repeated use.

7. Drug Interactions

Major Drug-Drug Interactions

NSAIDs:

• Anticoagulants (Warfarin, DOACs), Antiplatelets (Clopidogrel): Increased risk of bleeding due to additive effects on platelet function (non-selective NSAIDs) and potential GI ulceration.
• ACE Inhibitors, ARBs, Diuretics: NSAIDs can attenuate the antihypertensive effect and increase the risk of renal impairment due to inhibition of renal prostaglandin-mediated vasodilation.
• Lithium: NSAIDs can decrease renal clearance of lithium, leading to increased serum levels and potential toxicity.
• Other NSAIDs or Corticosteroids: Concomitant use significantly increases the risk of GI ulceration and bleeding.

Opioids:

• Other CNS Depressants (Benzodiazepines, Sedative-Hypnotics, Alcohol, Skeletal Muscle Relaxants): Concomitant use produces additive CNS and respiratory depression, significantly increasing the risk of profound sedation, respiratory arrest, coma, and death. This interaction carries a prominent Black Box Warning.
• MAO Inhibitors: Risk of serotonin syndrome or exaggerated opioid effects (excitatory or depressive). Generally contraindicated.
• Mixed Agonist-Antagonists (e.g., Pentazocine, Butorphanol): May precipitate withdrawal in patients physically dependent on full opioid agonists.

Muscle Relaxants:

• Tizanidine with CYP1A2 Inhibitors (e.g., Ciprofloxacin, Fluvoxamine): Potent inhibition of tizanidine metabolism can lead to dramatically increased plasma levels, causing severe hypotension and bradycardia. Concomitant use is contraindicated.
• Baclofen with other CNS Depressants: Additive sedation and respiratory depression.
• Dantrolene with other Hepatotoxic Drugs: Increased risk of liver injury.

Contraindications:

• NSAIDs: Active peptic ulcer disease, history of aspirin/NSAID-induced asthma or urticaria, severe renal impairment, third trimester of pregnancy (risk of premature ductus arteriosus closure).
• Opioids: Acute or severe bronchial asthma, gastrointestinal obstruction, paralytic ileus, significant respiratory depression (in unmonitored settings).
• Dantrolene: Active hepatic disease, when spasticity is used to maintain posture or balance.
• Tizanidine: Concomitant use with potent CYP1A2 inhibitors.

8. Special Considerations

Pregnancy and Lactation

Analgesics: Acetaminophen is generally considered the analgesic of choice for mild to moderate pain during pregnancy. NSAIDs should be avoided, particularly in the third trimester due to risks of premature ductus arteriosus closure, oligohydramnios, and delayed labor. Opioids may be used for severe pain but carry risks of neonatal withdrawal (Neonatal Abstinence Syndrome) with prolonged use. Most adjuvant analgesics (gabapentin, pregabalin, TCAs, SNRIs) require careful risk-benefit assessment; data are limited, and they are often avoided unless essential.

Muscle Relaxants: Most are not recommended during pregnancy due to limited safety data. Baclofen crosses the placenta, and risks versus benefits must be weighed. Botulinum toxin is classified as Pregnancy Category C; systemic absorption is minimal, but elective use is typically postponed.

Pediatric Considerations

Dosing is typically weight-based. Acetaminophen and ibuprofen are commonly used for pain and fever. Opioids require careful titration and monitoring for respiratory depression. The use of adjuvant neuropathic pain agents is less common and often off-label; gabapentin is used in some pediatric neuropathic pain conditions. For spasticity in cerebral palsy, baclofen (oral or intrathecal) and botulinum toxin are mainstays. Dantrolene is rarely used in children due to the risk of hepatotoxicity.

Geriatric Considerations

Age-related changes in pharmacokinetics (decreased renal/hepatic clearance, altered body composition) and pharmacodynamics (increased sensitivity to CNS effects) necessitate a “start low, go slow” approach.

• Analgesics: Increased risk of NSAID-induced GI bleeding and renal toxicity. Opioids cause more pronounced sedation, confusion, and constipation; risk of falls is significantly increased. Gabapentin and pregabalin require dose adjustment for reduced renal function and can cause dizziness and sedation, increasing fall risk.
• Muscle Relaxants: Centrally acting agents are often poorly tolerated due to sedation, confusion, and increased fall risk. They are generally avoided or used at very low doses. The Beers Criteria list most skeletal muscle relaxants as potentially inappropriate for older adults due to anticholinergic effects, sedation, and risk of fracture.

Renal and Hepatic Impairment

Renal Impairment:

• NSAIDs: Contraindicated in severe impairment; use with extreme caution in moderate impairment due to risk of worsening renal function and fluid retention.
• Opioids: Active metabolites of morphine and codeine can accumulate, leading to prolonged sedation and respiratory depression. Fentanyl, methadone, and buprenorphine may be safer alternatives, though still requiring caution.
• Gabapentin, Pregabalin, Baclofen: Require significant dose reduction or extended dosing intervals as they are renally excreted unchanged. Accumulation can cause severe CNS depression.

Hepatic Impairment:

• Acetaminophen: Dose must be reduced (typically to ≤2 g/day) or avoided in severe impairment due to reduced glutathione stores and increased risk of hepatotoxicity.
• Most NSAIDs, Opioids, Tizanidine, Dantrolene: Require caution or dose reduction due to reduced metabolism. Opioids may have an exaggerated effect due to decreased first-pass metabolism and possible accumulation of active metabolites.
• Methocarbamol, Carisoprodol: Metabolized to active compounds (e.g., carisoprodol to meprobamate) that may accumulate.

9. Summary/Key Points

• Pharmacotherapy in rehabilitation serves as a critical adjunct to physical modalities, primarily aimed at managing pain, spasticity, and inflammation to enable active participation in therapy.
• Drug selection should be guided by the specific pathophysiology (nociceptive vs. neuropathic pain, spasticity vs. muscle spasm) and a thorough assessment of patient comorbidities, age, and concomitant medications.
• The principle of using the lowest effective dose for the shortest necessary duration is paramount, particularly for opioids, NSAIDs, and centrally acting muscle relaxants, to minimize adverse effects and long-term complications.
• Pharmacokinetic alterations in geriatric patients and those with renal or hepatic impairment are common and necessitate careful dose adjustment and vigilant monitoring.
• Multimodal analgesia, combining agents with different mechanisms of action (e.g., NSAID + adjuvant neuropathic agent), often
  

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