Can a regimen including tenapanor (tenapanor), linaclotide (linaclotide), and various supplements such as lipo NMN (nicotinamide mononucleotide), TMG (trimethylglycine), resveratrol, and others cause skin itchiness, strange sensations, and mild excoriations in a patient with pre-diabetes and Irritable Bowel Syndrome with Constipation (IBS-C)?

Polypharmacy-Related Pruritus and Sensory Symptoms: Immediate Medication Review Required

This patient's skin itchiness, strange sensations in arms and torso, and mild excoriations without visible rash are highly concerning for drug-induced pruritus and should prompt immediate systematic medication review, with particular attention to niacin-containing supplements (NMN), berberine, and rapamycin as the most likely culprits.

Primary Suspects for Drug-Induced Pruritus

High-Risk Supplements in This Regimen

• Niacin/NMN (Nicotinamide Mononucleotide) is the most likely cause of pruritus and abnormal sensations, as niacin commonly causes flushing, pruritus, and paresthesias through prostaglandin-mediated mechanisms 1

• Berberine can cause pruritus and skin reactions in susceptible individuals, particularly at higher doses used for glycemic control 1

• Rapamycin (sirolimus) is associated with pruritus in 15% of patients and can cause skin toxicity including xerotic skin, which exacerbates itching 2, 1

• Resveratrol has limited safety data in humans, with insufficient evidence to rule out adverse cutaneous effects 3

Immediate Management Algorithm

Step 1: Discontinue Most Likely Offenders (Week 1)

• Stop NMN/niacin-containing supplements immediately - this is the single most likely cause of flushing-type pruritus with paresthesias 1

• Discontinue rapamycin temporarily - given its known association with pruritus and xerotic skin 2, 1

• Hold berberine - particularly if using doses >1000mg daily for pre-diabetes management 1

Step 2: Symptomatic Treatment During Washout Period

• Apply moderate-to-high potency topical corticosteroid (e.g., triamcinolone 0.1% cream) to affected areas twice daily for pruritus control 4

• Apply emollients at least once daily to the whole body to restore skin barrier function - use oil-in-water creams or ointments, avoiding alcohol-containing lotions 4, 5

• Use topical menthol 0.5% or cooling antipruritic lotions for immediate symptomatic relief of itching 4

• Consider diphenhydramine 25-50 mg or hydroxyzine 25-50 mg at bedtime only if nighttime pruritus is disrupting sleep 4

Step 3: Reassess After 2 Weeks

• If symptoms resolve completely - the discontinued medications were causative; do not restart them 4, 1

• If symptoms persist but improve - continue topical therapy and consider short-term oral systemic corticosteroids 4

• If no improvement - consider dermatology referral and evaluate for other causes including drug-induced cholestasis from metformin or other hepatotoxic supplements 1

Additional Concerning Drug Interactions

Metformin (Glucophage) Interactions

• Multiple supplements in this regimen may potentiate metformin's effects, increasing risk of lactic acidosis, particularly berberine which has additive glucose-lowering effects 3

• Monitor for signs of lactic acidosis including muscle pain, unusual fatigue, or respiratory distress given the combination of metformin with multiple metabolically active supplements 3

Rapamycin-Specific Concerns

• Weekly rapamycin use for "anti-aging" is off-label and carries significant immunosuppressive risks including increased infection susceptibility 1

• Rapamycin commonly causes xerotic skin (dry skin) in >50% of patients on long-term therapy, which directly exacerbates pruritus 2

Critical Pitfalls to Avoid

• Do not use topical calamine lotion or crotamiton cream - evidence shows they lack efficacy for drug-induced pruritus 4

• Avoid topical neomycin-containing preparations - neomycin causes sensitization in 5-15% of patients with chronic dermatitis and could worsen symptoms 4

• Do not assume antihistamines alone will resolve drug-induced pruritus - they are specifically effective for urticaria but have limited efficacy when histamine is not the primary mediator 4, 1

• Avoid hot showers and excessive soap use - these cause skin dehydration and worsen pruritic symptoms 4

Monitoring for Serious Complications

• Watch for secondary bacterial infection from excoriations, which requires topical or systemic antibiotics 4

• Monitor closely given pre-diabetes status - patients with diabetes have increased risk of secondary bacterial infection from skin breakdown 4

• Assess for sleep disturbance and quality of life impact - severe pruritus commonly affects these domains and may require more aggressive intervention 6

Long-Term Supplement Rationalization

This patient is taking 30+ supplements/medications simultaneously, creating substantial risk for:

• Drug-drug interactions that are impossible to predict with this level of polypharmacy 1
• Cumulative hepatotoxic effects from multiple supplements processed through similar pathways 1
• Difficulty identifying causative agents when adverse events occur 1

Strongly recommend systematic reduction to evidence-based therapies only: metformin for pre-diabetes, linaclotide or tenapanor for IBS-C, and vitamin D if deficient 2, 3