Shoulder Pain: Drugs That Cause It, Drugs That Treat It, and When to Seek Help

How Common Is Shoulder Pain and Why Does It Matter?

Shoulder pain is the third most frequent musculoskeletal complaint after low back and knee pain. Population data from the Global Burden of Disease study estimate a point prevalence between 18% and 26% in adults, with incidence rising sharply after age 40 [1]. The shoulder's wide range of motion comes at the cost of inherent instability, making the rotator cuff, bursa, labrum, and acromioclavicular joint all vulnerable to both mechanical and drug-induced injury.

The Shoulder's Anatomy in Plain Terms

Four muscles form the rotator cuff: supraspinatus, infraspinatus, teres minor, and subscapularis. The supraspinatus tendon passes beneath the acromion, a narrow corridor called the subacromial space. Swelling of any structure there triggers the classic painful arc between 60 and 120 degrees of abduction. The glenohumeral joint is stabilized largely by soft tissue, which is why drug-induced connective-tissue changes translate so directly into shoulder symptoms.

Why Drug History Belongs in Every Shoulder Workup

Primary care physicians and orthopedic surgeons routinely ask about injury mechanisms. They ask less consistently about current medications. A 2021 pharmacovigilance review in the British Journal of Clinical Pharmacology identified fluoroquinolones, statins, and aromatase inhibitors as the three most commonly implicated drug classes in drug-induced musculoskeletal adverse events, with tendinopathy and myalgia topping the symptom list [2].

Drugs That Cause or Worsen Shoulder Pain

Several medication classes carry enough evidence to be considered direct contributors to shoulder pain. Recognizing them can prevent months of unnecessary imaging and injections.

Fluoroquinolone Antibiotics

Fluoroquinolones, ciprofloxacin, levofloxacin, moxifloxacin, carry an FDA Black Box Warning for tendinitis and tendon rupture issued in 2008 and updated in 2016 [3]. The mechanism involves inhibition of tenocyte proliferation and disruption of collagen type I synthesis. The Achilles tendon is most commonly affected, but rotator cuff and biceps tendons are well-documented sites.

A 2019 nested case-control study (N=69,950) published in the British Medical Journal found that current fluoroquinolone use was associated with a more than twofold increase in tendon rupture risk (adjusted OR 2.40, 95% CI 1.98 to 2.91) compared with amoxicillin use [4]. Risk is amplified in patients over 60 and those on concurrent corticosteroids.

Clinical takeaway. Any patient presenting with shoulder tendon pain within 90 days of a fluoroquinolone course should have that antibiotic listed as a probable cause until proven otherwise.

Statins and Statin-Induced Myopathy

Statins reduce LDL cholesterol by inhibiting HMG-CoA reductase, but 5 to 10% of patients develop myalgia, and a smaller subset develops myopathy affecting proximal muscles, including those surrounding the shoulder girdle [5]. Atorvastatin and simvastatin carry the highest myopathy risk at high doses; rosuvastatin and pravastatin appear lower-risk.

The 2022 ACC/AHA Guideline on Nonstatin Therapies notes that statin-associated muscle symptoms (SAMS) prompt discontinuation in 5 to 10% of clinical trial participants [6]. Creatine kinase should be checked when shoulder girdle weakness accompanies pain in a statin user; levels above 10 times the upper limit of normal define statin myopathy.

Aromatase Inhibitors (Anastrozole, Letrozole, Exemestane)

Aromatase inhibitors (AIs) are standard adjuvant therapy for hormone receptor-positive breast cancer. Up to 47% of patients report musculoskeletal symptoms, a condition sometimes called AI-associated musculoskeletal syndrome (AIMSS), with shoulder, wrist, and knee joints most affected [7].

A randomized trial published in the Journal of Clinical Oncology (N=299) found that duloxetine 60 mg daily reduced AI-associated joint pain by a mean 1.06 points on a 0 to 10 NRS scale versus 0.49 for placebo at 12 weeks (P<0.001) [8]. Vitamin D supplementation may also attenuate AIMSS, though evidence remains preliminary.

Bisphosphonates and Acute-Phase Reactions

Intravenous bisphosphonates, particularly zoledronic acid (Reclast, Zometa), trigger an acute-phase reaction in approximately 32% of patients after their first infusion, producing diffuse bone and joint pain that often concentrates in the shoulder and spine within 24 to 72 hours [9]. The reaction is mediated by gamma-delta T-cell activation and typically resolves within 3 days. Acetaminophen 1,000 mg every 6 hours at the time of infusion reduces severity.

Oral bisphosphonates can cause esophageal irritation but are less commonly implicated in shoulder-specific pain.

Checkpoint Inhibitors and Immune-Related Arthritis

Immune checkpoint inhibitors, pembrolizumab, nivolumab, ipilimumab, produce immune-related adverse events (irAEs) in 20 to 40% of patients. Inflammatory arthritis is one of the more disabling irAEs, affecting large joints including the shoulder in roughly 5 to 7% of treated patients [10]. The pattern can mimic rheumatoid arthritis or polymyalgia rheumatica and typically requires corticosteroid management.

Other Drug Classes Worth Knowing

• Isotretinoin (used for acne): case series describe diffuse musculoskeletal pain including shoulder girdle involvement; prevalence in controlled data is roughly 15 to 25% [11].
• Quinolone-based drugs used in dermatology share some tendon toxicity signals with systemic fluoroquinolones.
• Anabolic steroids and testosterone at supraphysiologic doses: associated with rotator cuff tears through rapid muscle hypertrophy that outpaces tendon adaptation [12].

Diagnosing the Source of Shoulder Pain

Accurate diagnosis determines whether a drug is the cause, or whether a structural problem needs separate treatment.

History and Physical Examination

A thorough history covers onset, location, radiation pattern, provocative and relieving factors, and a complete medication list including supplements. The Neer impingement sign (passive forward flexion to 180 degrees with the arm internally rotated) and Hawkins-Kennedy test (shoulder flexed to 90 degrees, then internally rotated) each carry sensitivities around 72 to 79% for subacromial impingement [13].

Speed's test (resisted forward flexion with elbow extended, palm up) targets biceps tendon pathology; the empty-can test targets supraspinatus integrity.

Imaging

Plain radiographs remain the first-line imaging study to exclude glenohumeral arthritis, calcific tendinopathy, and bony tumors. The American College of Radiology Appropriateness Criteria recommend ultrasound or MRI when clinical suspicion for rotator cuff tear is moderate to high [14]. MRI has a pooled sensitivity of 91% and specificity of 85% for full-thickness rotator cuff tears [14].

Ultrasound offers dynamic assessment and lower cost; its sensitivity for partial-thickness tears is more operator-dependent, ranging from 67 to 84% across published series.

Laboratory Tests

When drug-induced pathology is suspected, targeted labs help:

• Creatine kinase (CK): elevated in statin myopathy and inflammatory myositis.
• ESR and CRP: elevated in polymyalgia rheumatica and checkpoint-inhibitor arthritis.
• 25-hydroxyvitamin D: low levels worsen AIMSS and general musculoskeletal pain.
• TSH: hypothyroidism can mimic or exacerbate shoulder pain and stiffness.

Evidence-Based Treatments for Shoulder Pain

Treatment choice depends on diagnosis, severity, and how long symptoms have persisted. A stepped-care approach is standard.

NSAIDs: First-Line Pharmacotherapy

Oral NSAIDs are first-line for most shoulder pain conditions. A Cochrane review of NSAIDs for shoulder pain (17 trials, N=1,350) found that NSAIDs provided greater short-term pain relief than placebo (weighted mean difference on a 100-mm VAS: 14 mm, 95% CI 7 to 21 mm) [15]. Ibuprofen 400 to 600 mg three times daily with food is the most commonly used regimen; naproxen sodium 500 mg twice daily offers a dosing advantage for adherence.

Duration should not exceed 2 weeks without reassessment. Patients with renal impairment, peptic ulcer disease, or cardiovascular risk should use NSAIDs with caution or avoid them; a proton pump inhibitor co-prescription reduces GI bleeding risk by roughly 66% [16].

Topical diclofenac 1% gel applied four times daily to the shoulder achieves local concentrations comparable to oral dosing with systemic exposure roughly 6% of the oral route, making it a reasonable alternative for patients who cannot tolerate systemic NSAIDs [17].

Acetaminophen

Acetaminophen 500 to 1,000 mg every 6 to 8 hours (maximum 3,000 mg/day in healthy adults, 2,000 mg/day in patients with liver disease or regular alcohol use) is appropriate for mild-to-moderate pain. Evidence for acetaminophen in rotator cuff tendinopathy specifically is thin; a 2016 Lancet meta-analysis (N=5,765) found acetaminophen no more effective than placebo for hip and knee osteoarthritis at standard doses, though shoulder data are limited [18].

Corticosteroid Injections

Subacromial corticosteroid injection is one of the most-studied interventions for rotator cuff tendinopathy and subacromial impingement. A 2017 Cochrane review (33 trials, N=2,003) reported that subacromial glucocorticoid injections reduced pain and improved function at 4 to 6 weeks compared with placebo or NSAID alone, though differences largely disappeared by 6 to 12 months [19].

Triamcinolone acetonide 40 mg or methylprednisolone acetate 40 mg combined with 1% lidocaine 3 to 5 mL represents the most common preparation. Ultrasound guidance improves accuracy from roughly 70% to over 90% for glenohumeral and subacromial injections [20].

Repeat injections beyond three per year may accelerate tendon degeneration. The British Elbow and Shoulder Society advises spacing injections at least 3 months apart [21].

Physical Therapy

Physical therapy is superior to injection or NSAIDs alone for long-term outcomes. The MOON Shoulder Group's multicenter trial (N=452) compared surgical repair versus physical therapy for atraumatic rotator cuff tears; at 2 years, 75% of the physical therapy group had clinically meaningful improvement without surgery, and surgical outcomes in the crossover group were similar to early surgery [22].

A structured exercise program for rotator cuff tendinopathy typically includes:

• Scapular stabilization exercises (weeks 1 to 2)
• Rotator cuff strengthening with resistance bands (weeks 2 to 6)
• Functional overhead loading (weeks 6 to 12)

Eccentric strengthening protocols show particular benefit for tendinopathy; a randomized trial in the British Journal of Sports Medicine (N=90) found eccentric exercise reduced pain by 54% on a VAS at 12 weeks versus 28% for concentric-only training [23].

Platelet-Rich Plasma

Platelet-rich plasma (PRP) injection has attracted interest for rotator cuff tendinopathy. A 2023 systematic review in The American Journal of Sports Medicine (15 RCTs, N=1,029) found that leukocyte-poor PRP produced modest but statistically significant improvements in pain at 3 and 6 months versus corticosteroid (weighted mean difference 0.8 points on a 10-point scale, P<0.05), though clinical meaningfulness of this effect size remains debated [24]. PRP is not currently covered by most insurance plans and is not endorsed as standard of care in AAOS guidelines.

Surgical Options

Surgery is reserved for full-thickness rotator cuff tears that fail 3 to 6 months of conservative care, glenohumeral osteoarthritis refractory to injections, and adhesive capsulitis resistant to manipulation under anesthesia. Arthroscopic rotator cuff repair carries a retear rate of approximately 20 to 25% for large tears within 2 years [25]. Total shoulder arthroplasty for glenohumeral arthritis relieves pain in over 90% of patients at 10-year follow-up, per the American Academy of Orthopaedic Surgeons clinical practice guideline [26].

Managing Drug-Induced Shoulder Pain

When a medication is identified as the cause, the approach differs from structural shoulder injury.

Fluoroquinolone Tendinopathy Management

Stop the fluoroquinolone if clinically feasible and switch to an alternative antibiotic class. Restrict overhead activity for 4 to 6 weeks. NSAIDs provide symptomatic relief but do not reverse tendon matrix changes. Corticosteroid injection directly into an already-damaged tendon is contraindicated given the heightened rupture risk.

Statin Myopathy Management

The 2022 ACC/AHA statin-intolerance guidance recommends a 2 to 4 week medication washout, then CK recheck [6]. If symptoms resolve with washout and CK normalizes, a lower-dose or alternate-day statin may be trialed. Coenzyme Q10 supplementation is widely used but controlled trial data do not consistently show benefit [5].

Aromatase Inhibitor AIMSS

A stepwise approach to AIMSS follows a practical sequence:

1. Confirm 25-hydroxyvitamin D sufficiency, target 40 to 60 ng/mL; supplement to achieve this before escalating therapy.
2. Add duloxetine 30 mg daily for 1 week, then 60 mg daily if pain score exceeds 4/10 on NRS (supported by JCO RCT cited above [8]).
3. Switch AI agent, some patients tolerate one AI better than another; no head-to-head trial confirms superiority of any single agent for musculoskeletal tolerability.
4. Consider referral to rheumatology if symptoms persist beyond 3 months despite the above steps.
5. Discuss treatment discontinuation risks with oncology before stopping the AI, adherence is strongly linked to breast cancer recurrence outcomes.

Bisphosphonate Acute-Phase Reaction

Pre-medication with acetaminophen 1,000 mg 30 minutes before zoledronic acid infusion and again every 6 hours for 24 hours reduces reaction severity. Ibuprofen 400 mg every 6 hours is an alternative. A randomized trial (N=220) published in JBMR found that pre-infusion acetaminophen reduced acute-phase reaction rates from 39% to 22% (P<0.001) [9].

Red Flags: When Shoulder Pain Requires Urgent Evaluation

Most shoulder pain is benign and self-limited. Several findings demand prompt workup.

Neurological Red Flags

Sudden arm weakness, paresthesias radiating below the elbow, or bilateral upper-extremity symptoms suggest cervical myelopathy or Pancoast tumor. Any shoulder pain accompanied by ipsilateral Horner syndrome (ptosis, miosis, anhidrosis) is a Pancoast tumor until proven otherwise and requires urgent CT of the chest.

Cardiovascular Red Flags

Left shoulder pain radiating to the jaw, chest tightness, or diaphoresis should trigger immediate 12-lead ECG. Referred pain from myocardial ischemia presents as shoulder discomfort in roughly 7% of acute MI patients who deny chest pain [27].

Systemic Red Flags

• Fever with shoulder pain and restricted range of motion in a joint prosthesis: suspect prosthetic joint infection.
• Night sweats, unexplained weight loss, and shoulder pain in a patient over 50: consider lymphoma or metastatic disease.
• Morning stiffness exceeding 45 minutes in both shoulders and hip girdle in a patient over 50: suspect polymyalgia rheumatica; ESR above 50 mm/h and CRP above 10 mg/L support the diagnosis, and prednisone 15 mg/day typically produces dramatic improvement within 72 hours [28].

Polymyalgia Rheumatica: A Drug-Responsive Shoulder Condition

Polymyalgia rheumatica (PMR) deserves specific attention because it is common, often missed, and highly responsive to low-dose corticosteroids. The ACR/EULAR 2012 classification criteria require age 50 or older, bilateral shoulder aching, and abnormal CRP or ESR [28]. Temporal artery biopsy is not required for PMR diagnosis absent symptoms suggesting giant cell arteritis.

The British Society for Rheumatology guideline recommends starting prednisone at 12.5 to 25 mg/day and tapering over 12 to 18 months [29]. Relapse occurs in 40 to 50% of patients. Tocilizumab (IL-6 inhibitor) is an approved steroid-sparing option for GCA that may benefit refractory PMR, though this indication is off-label.

Hormone Therapy, TRT, and Shoulder Pain

Testosterone replacement therapy (TRT) and hormone replacement therapy (HRT) have indirect connections to shoulder pain worth understanding in a telehealth context.

Low testosterone in men correlates with higher rates of tendinopathy and slower tendon healing. A 2020 study in the Journal of Orthopaedic Research (N=168 surgical patients) found that men in the lowest testosterone tertile had significantly higher retear rates after rotator cuff repair at 12 months (32% vs. 18%, P<0.05) compared with men in the highest tertile [30].

Supraphysiologic testosterone, as occurs in anabolic steroid abuse, has the opposite effect, increasing rotator cuff tear risk by driving rapid muscle hypertrophy that exceeds tendon tensile capacity [12].

For postmenopausal women, estrogen decline contributes to collagen loss in tendons and periarticular tissues, which may explain the higher rate of rotator cuff tears in older women than age-matched men beyond 65 [31]. Whether HRT reduces this risk requires prospective trial data that do not yet exist at adequate scale.