What medication regimen would you recommend for my generalized full-body stiffness, given that pregabalin, duloxetine, amitriptyline, thiocolchicoside, and tolperisone have been ineffective, baclofen provides relief, tizanidine causes sedation, and tramadol works well, and I suspect the pain is peripheral rather than fibromyalgia?

Medication for Full-Body Stiffness with Suspected Peripheral Pain Mechanism

Continue baclofen as your primary muscle relaxant and add tramadol for breakthrough pain, while avoiding further trials of centrally-acting neuropathic agents, since your response pattern strongly suggests a peripheral musculoskeletal mechanism rather than fibromyalgia. 1

Why Your Response Pattern Matters

Your medication response profile is diagnostically informative:

• Baclofen works effectively because it acts directly on GABA-B receptors in the spinal cord to reduce muscle spasticity and stiffness at the tissue level, not through central pain modulation 1
• Tramadol works brilliantly because it provides both mu-opioid receptor activation and monoamine reuptake inhibition, addressing peripheral nociceptive pain rather than central sensitization 2, 1
• Complete failure of pregabalin, duloxetine, and amitriptyline (the three first-line fibromyalgia medications with Level Ia, Grade A evidence) strongly argues against fibromyalgia, which is characterized by central sensitization and typically responds to these agents 1, 3, 4

The European League Against Rheumatism explicitly states that fibromyalgia medications target abnormal central pain processing, not peripheral tissue pathology 1, 3. Your 0% response to all three classes suggests your pain does not originate from central sensitization.

Recommended Medication Regimen

Primary Muscle Relaxant: Baclofen

• Continue baclofen at your current effective dose as the cornerstone of therapy for generalized muscle stiffness 1
• Baclofen is the most appropriate muscle relaxant for diffuse spasticity because it directly inhibits polysynaptic and monosynaptic reflexes at the spinal level 1
• If sedation becomes problematic, divide the total daily dose into 3-4 smaller doses rather than switching agents 1

Analgesic for Breakthrough Pain: Tramadol

• Use tramadol 50-100 mg every 4-6 hours as needed for pain that baclofen does not fully control 2, 1
• The European League Against Rheumatism recommends tramadol with Level Ib, Grade A evidence when first-line medications are ineffective, which applies to your case 1
• Tramadol has a moderate effect size of 0.657 for pain reduction and works through dual mechanisms: weak opioid activity plus serotonin-norepinephrine reuptake inhibition 1
• Maximum daily dose should not exceed 400 mg 2, 1

What NOT to Add

• Do not add gabapentin because it shares the same α2-δ calcium channel mechanism as pregabalin, which already failed completely in your case 4
• Avoid cyclobenzaprine because although it has Level Ia, Grade A evidence for fibromyalgia, it is structurally similar to amitriptyline (which failed for you) and works through central mechanisms 1
• Never use strong opioids or corticosteroids as they lack efficacy for chronic musculoskeletal conditions and cause significant harm 1, 3, 4
• Do not use NSAIDs as monotherapy because they have no proven benefit over placebo for generalized stiffness and carry cardiovascular and renal risks 1

Why Tizanidine Causes Excessive Sedation

Tizanidine is an α2-adrenergic agonist that reduces muscle tone but has much greater central nervous system penetration than baclofen, causing pronounced sedation in most patients 1. Since baclofen provides effective relief without this side effect, there is no reason to switch.

Diagnostic Reconsideration

Your response pattern suggests you may have:

• Generalized muscle spasticity or stiffness syndrome of peripheral origin rather than fibromyalgia 1, 3
• Possible underlying inflammatory or autoimmune myopathy that warrants rheumatologic evaluation with creatine kinase, aldolase, inflammatory markers (ESR, CRP), and autoantibody panel 3
• Mechanical musculoskeletal pain from postural dysfunction or biomechanical abnormalities that would benefit from physical therapy 1

The American College of Rheumatology criteria for fibromyalgia require widespread pain plus abnormal central pain processing that responds to centrally-acting medications 3. Your complete non-response to three different classes of central agents (tricyclic, SNRI, and α2-δ ligand) makes fibromyalgia highly unlikely.

Critical Monitoring Parameters

• Assess pain intensity and functional status every 4 weeks using a 0-10 numeric rating scale 1, 4
• Monitor for opioid-related risks with tramadol, including constipation, nausea, and potential for dependence, though tramadol has lower abuse potential than traditional opioids 2, 1
• Watch for baclofen withdrawal if doses are missed, as abrupt discontinuation can cause seizures and hallucinations; always taper gradually over 2-4 weeks if stopping 1
• Evaluate for underlying systemic disease if stiffness worsens or new symptoms develop 3

Non-Pharmacological Adjuncts

• Heated pool therapy 2-3 times weekly has Level IIa, Grade B evidence for reducing muscle stiffness and improving function 1
• Progressive resistance training targeting major muscle groups can address deconditioning that perpetuates stiffness 1
• Physical therapy evaluation to identify and correct biomechanical contributors to generalized stiffness 1

These interventions complement medication by addressing peripheral tissue dysfunction rather than central pain processing.