Tizanidine, an imidazole derived α2 adrenergic agonist, is widely prescribed for spasticity and chronic musculoskeletal pain. Abrupt discontinuation can precipitate withdrawal syndromes characterized by sympathetic overactivity. Although pharmacologically plausible, this phenomenon is potentially underreported in clinical practice. We describe four patients with diverse comorbidities who developed acute tizanidine withdrawal. All cases were directly observed at a single tertiary care center and identified during routine inpatient clinical practice over a defined timeline. Case 1 was a 24 year old female admitted with empagliflozin induced diabetic ketoacidosis who experienced hypertensive crisis and tachycardia following abrupt cessation of chronic high dose tizanidine. Case 2 was a 29 year old female with Crohn's disease who developed tremors, anxiety, and autonomic instability after reducing her regimen from 40 mg nightly to 16 mg daily. She had self-discontinued her last dose prior to presentation. Case 3 was a 29 year old female with recurrent pancreatitis, resistant hypertension, and an adrenal incidentaloma who presented with severe hypertension and tremors after discontinuing both tizanidine and diazepam. Symptoms began within approximately 24 h of abrupt cessation. Case 4 was a 42 year old male with asthma, hypertension, anxiety disorder, bariatric surgery, methamphetamine use, and more than ten prior admissions specifically for tizanidine withdrawal, who presented with palpitations, tremors, vomiting, and hypertensive crisis after abrupt dose reduction. In all cases, reintroduction of tizanidine followed by a structured tapering regimen resulted in clinical stabilization. These cases highlight the clinical significance of tizanidine withdrawal, its diverse presentations, and the importance of cautious tapering. Patient education on avoiding abrupt discontinuation is essential, particularly for individuals with psychiatric comorbidities or prior withdrawal episodes. Awareness of this underrecognized syndrome is critical to prevent misdiagnosis and ensure safe prescribing practices.
Relapsed/refractory multiple myeloma (RRMM) has been transformed by T-cell-redirecting immunotherapies, including chimeric antigen receptor T-cell therapy and bispecific antibodies. Despite unprecedented response rates in heavily pretreated patients, these treatments impose complex and sustained toxicities, substantial logistical demands, and existential distress. Palliative care integration in this setting remains underexplored. We conducted a narrative synthesis using a systematic-style search of PubMed/MEDLINE and Web of Science, identifying 315 records. After deduplication and title and abstract screening, 51 reports underwent full-text review. Eighteen primary studies were included, and 12 supplementary references were added for contextual support, yielding 30 citations overall. Six thematic domains emerged: the relevance of palliative care in RRMM; quality of life and patient-reported outcomes; supportive and palliative care challenges during immunotherapy; communication and shared decision-making; caregiver burden; and practical models for integration. Early, concurrent palliative care integration in RRMM immunotherapy is warranted and feasible and should be evaluated prospectively.
The management of cancer pain in older adults with hydromorphone requires careful consideration. This systematic review evaluates the current evidence regarding the efficacy and safety of hydromorphone in this population. The review protocol follows the PRISMA 2020 guidelines and the PICO framework. The search strategy used terms including "hydromorphone," "cancer pain," and "older adults" across four databases. Primary studies published between 2014 and 2024 in English, Spanish, French, Italian, and Portuguese were included. Data extraction was limited to studies involving patients older than 60 years. Qualitative studies and those lacking methodological rigor were excluded. Standardized instruments were used to assess the risk of bias. Of the 332 records initially identified, seven observational studies (retrospective cohorts and cross-sectional analyses) met the inclusion criteria, for a total of 41,608 patients. According to the GRADE methodology, the certainty of evidence regarding efficacy and safety was rated as low to very low due to high risk of bias and methodological heterogeneity. Evidence regarding the efficacy and safety of hydromorphone for cancer pain in older adults shows very low certainty. Routine clinical use requires caution. High-quality, randomized controlled trials are needed to guide clinical decision-making.
Atrial fibrillation (AF) is prevalent in hospice care, but anticoagulation decisions in this population are not well understood. In this cross-sectional study, we described the prevalence and characteristics associated with direct oral anticoagulant (DOAC) prescription on hospice admission. We used electronic health data from adult decedents with AF in a large, for-profit hospice chain in the United States between January 1, 2017 and December 31, 2019. We used multivariable logistic regression with results reported as adjusted odds ratios (AORs) and 95% confidence intervals (CIs). Among 13,233 decedents, mean (standard deviation [SD]) age was 84.2 (9.9) years, 53.6% were female, 65.1% were White, and 56.1% were referred to hospice from a hospital. Mean (SD) CHA2DS2-VASc score were 3.8 (1.4) for males and 4.8 (1.3) for females, and mean (SD) HAS-BLED score was 2.2 (1.0). Overall, 8% of patients received a DOAC prescription on hospice admission. Characteristics associated with receiving a DOAC prescription included PPS scores of ≥ 20% (compared to scores < 20%), and receiving hospice care at home, nursing home, assisted living facility, or residential care home (compared to inpatient hospice). Further studies about the risks and benefits of DOAC use are needed to optimize decision-making in this population.
This review aimed to evaluate the efficacy and safety of subcutaneous nonsteroidal anti-inflammatory drugs (NSAIDs). We searched CENTRAL, MEDLINE, Embase, trial registries, and Google Scholar until December 19, 2024. Eligible studies were randomized controlled trials (RCTs) in adults comparing subcutaneous NSAIDs with other routes of administration, placebo, no treatment, or other drugs. The primary outcome was pain intensity; secondary outcomes were rescue medication use and adverse events. We assessed risk of bias using the Risk of Bias 2 tool. Random-effects meta-analyses used standardized mean differences (SMDs) for pain intensity and odds ratios for rescue medication use. Adverse events were summarized narratively. Four RCTs (n = 825) were included: three placebo-controlled trials and one route-comparison trial, all evaluating short-term treatment for acute pain with subcutaneous diclofenac or ketorolac. In the meta-analysis of three placebo-controlled trials (n = 500), subcutaneous NSAIDs reduced pain (SMD = 0.72; 95% CI, 0.22 to 1.21; I2 = 82.8%) and rescue medication use. Adverse-event data were limited and inconsistent, with one trial reporting higher event rates with subcutaneous NSAIDs than placebo and another reporting comparable rates. The route-comparison trial showed comparable efficacy and safety between subcutaneous and intramuscular diclofenac. In conclusion, subcutaneous diclofenac and ketorolac may reduce short-term acute pain compared with placebo. However, the evidence is limited and safety remains uncertain. Further route-comparison studies are needed.
Opioid-induced adrenal insufficiency is an underrecognized form of secondary adrenal insufficiency caused by hypothalamic-pituitary-adrenal axis suppression and a potential but overlooked cause of chronic diarrhea. We describe a 59-year-old woman with six months of diarrhea, abdominal pain, weight loss, hypotension, and hyponatremia extensively evaluated but unrevealing for gastrointestinal etiology. Biochemical testing confirmed secondary adrenal insufficiency. Medication review revealed prior buprenorphine-naloxone exposure. Hydrocortisone therapy resulted in rapid hemodynamic improvement and resolution of gastrointestinal symptoms. Chronic gastrointestinal complaints are not always gastrointestinal in origin and should prompt consideration of endocrine etiologies, particularly in patients with opioid exposure.
To assess the real-world effectiveness and tolerability of stepwise titration with compounded topical menthol in refractory localized neuropathic pain. We conducted a multicenter retrospective chart review in two French pain centers between March 2022 and September 2023. Adults with localized neuropathic pain, baseline pain intensity >4/10, DN4 ≥ 4, and previous treatment failure or intolerance received pharmacy-compounded menthol cream titrated from 1% to 10% over approximately 60 days. The primary endpoint was responder rate at the final concentration used, defined as ≥30% reduction in numerical rating scale pain intensity and/or ≥30% self-reported pain relief. Twenty-one patients were analyzed; 76% were women and 71% had chemotherapy-induced peripheral neuropathy. Mean pain intensity decreased from 6.83 at baseline to 4.82 at 10%, with significant improvement from 3% onward. At 10%, 12/21 patients met the response criterion. Treatment was generally well tolerated, with mostly mild transient local adverse effects. Progressively titrated topical menthol up to 10% may be a practical, accessible, and well-tolerated option for refractory localized neuropathic pain when systemic therapies are ineffective or poorly tolerated. These exploratory findings support titration-based use and warrant randomized placebo-controlled studies to confirm efficacy, refine dosing, and identify responder phenotypes.
Codeine is a prodrug opioid whose analgesic efficacy depends on its bioactivation into morphine via cytochrome P450 2D6. Its use in migraine is discouraged because of limited efficacy, tolerance, and the risk of medication-overuse headache. Drug-drug interactions affecting its metabolism may further compromise pain control. We report the case of a 72-year-old man with chronic migraine and daily codeine use. A pharmacist-led medication review identified a potential pharmacokinetic interaction between codeine and extended-release nicardipine. Plasma concentrations of codeine and its metabolites were measured before and after codeine intake under nicardipine treatment and three months after substitution with candesartan. The fold increase in morphine-glucuronide concentration between baseline and peak rose from 1.6 with nicardipine to 3.5 after discontinuation, consistent with restored codeine bioactivation. This case highlights a clinically relevant interaction between nicardipine and codeine leading to reduced opioid efficacy. Beyond tolerance and medication-overuse headache, pharmacokinetic interactions should be systematically considered in patients with refractory pain.
To examine whether a palliative care pocket manual revision suggesting suvorexant for nocturnal awakening was associated with changes in suvorexant prescription-record rates. We conducted a single-center retrospective interrupted time series study at a Toyama University Hospital using weekly prescription records for suvorexant (15 mg and 20 mg tablets combined). Prescription records, not unique patients, were analyzed with segmented negative binomial regression using an offset for days per week. The manual was updated on 16 May 2025; the first post-implementation week was 19 May 2025. The primary all-hospital series included 105 wk and 3,927 records. The immediate level change was in the direction of increase but statistically uncertain (IRR 1.34, 95% CI 0.88 to 2.05; p = 0.177), with no slope change (IRR per week 1.00, 95% CI 0.98 to 1.02; p = 0.888). Outpatient prescription-record rates showed a modest immediate increase (IRR 1.38, 95% CI 1.01 to 1.90; p = 0.043), whereas inpatient estimates were imprecise. Outpatient sensitivity analyses reduced statistical clarity. This local pharmacotherapy guidance revision coincided mainly with a secondary outpatient prescribing signal. Causality, clinical utility, and patient outcomes cannot be inferred.
Bone is a frequent site of metastasis, particularly in breast, lung, prostate, and renal cancers. Skeletal metastases lead to severe pain, fractures, hypercalcemia, and reduced quality of life. Zoledronic acid(ZA), a potent intravenous bisphosphonate, inhibits osteoclast-mediated bone resorption and may reduce metastatic bone pain. This study assessed the efficacy and safety of intravenous zoledronic acid in relieving bone pain in patients with bone metastases receiving standard analgesics. In this randomized prospective controlled study, out of 120, 70 adults aged 30-70 years with confirmed bone metastases and visual analog score of >4 who completed the follow up were enrolled. Patients were randomized into two groups (35 each), Group Z received ZA 4 mg intravenously (every 4 wk) along with low-dose morphine 5 mg every 4 h and tablet etoricoxib 60 mg twice daily and Group P received tab morphine 5 mg every 4 h and tab etoricoxib 60 mg twice daily. All patients received calcium and vitamin D supplementation. Weekly assessments included BPI scores, skeletal-related events, and adverse effects. Patients receiving intravenous ZA demonstrated significantly greater reductions in pain severity and fewer skeletal-related events than Group P (p < 0.05). No serious drug-related adverse effects were noted.
Sleep deprivation is a common concern for cancer patients. It has proven difficult to determine severity of sleep disturbances in a cancer group. Patients may fail to mention insomnia because they assume it is a common and temporary reaction to a cancer diagnosis or treatment, a condition that is frequently overlooked in cancer management. This prospective, double-blind, randomized comparative trial evaluated the efficacy and safety of oral melatonin (3 mg/day) versus oral olanzapine (5 mg/day) in 60 advanced cancer patients with insomnia over four weeks. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and Athens Insomnia Scale (AIS) at baseline, 2nd wk, and 4th wk. Both groups demonstrated significant, time-dependent improvement in sleep parameters (p < 0.001). Melatonin showed statistically significant superiority over olanzapine in PSQI scores at week four and overall AIS scores across all time points; however, melatonin exhibited a more favorable adverse effect profile, while olanzapine was associated with somnolence, akathisia, and weight gain. Both agents are effective for cancer-related insomnia symptoms, with melatonin offering a superior tolerability advantage in the palliative setting. Larger placebo-controlled trials with objective sleep measures are warranted to confirm these findings.
Chronic pain is highly prevalent in older adult cancer survivors, but the prevalence of nociplastic pain is ill-defined. This is important because nociplastic pain responds poorly to opioids, the cornerstone of cancer pain management. Moreover, older adults face high risk of respiratory depression, falls, and mortality from opioids. Given these risks, a better understanding of nociplastic pain prevalence is needed. This was a cross-sectional analysis study at a large, academic medical center. Patients ≥65 years of age with at least one outpatient visit between November 1, 2015 and December 23, 2021 were included. The primary outcome was the proportion of older adults, with and without cancer, with a chronic overlapping pain condition (COPC) diagnosis (a type of nociplastic pain). There were 320,727 older adults included and 15.5% carried at least one COPC diagnosis. Those with COPCs were more likely to be female, younger, and have a higher Elixhauser Comorbidity Index. Black Americans were less likely to carry a COPC diagnosis. The incidence rate of COPCs was 1.0333 times higher in older adults with cancer (95% CI [1.014, 1.053], p = 0.001). One in six older adults had a COPC diagnosis. Those with cancer were more likely to carry a COPC diagnosis than their peers without.
