Opioids, Sedatives and Perioperative Drugs

OPBSPharmacology

Recent JBJS and Bone and Joint Journal reviews on opioids, sedatives and perioperative drugs, summarised for the OPBS exam. See also Pharmacology.

Recent Review. Opioid Stewardship in Arthroplasty

  • Opioids act on mu, kappa and delta receptors, blocking pain transmission and activating reward circuits.
  • Long-term use brings tolerance, physical dependence with withdrawal on stopping, and potential misuse.
  • Opioid-induced hyperalgesia is a paradoxical rise in pain sensitivity, partly through NMDA receptor activation and central sensitisation.
  • Cardiac or respiratory disease and obstructive sleep apnoea are risk factors for opioid-induced respiratory depression.
  • Preoperative opioid use is the strongest predictor of persistent use at 6 months, raising the odds 7 to 15 fold.
  • Preoperative users have nearly twice the risk of periprosthetic fracture, aseptic loosening and dislocation.
  • In March 2025 the UK MHRA removed postoperative pain as a licensed indication for all prolonged-release opioids.
  • Modified-release opioids give no better analgesia than immediate-release forms and carry more respiratory depression, sedation, confusion and falls.
  • Opioid stewardship borrows antimicrobial stewardship principles to make opioid prescribing safer and accountable.
More on stewardship measures
  • About a quarter of adults aged 65 years or more use opioids for 90 days or longer, with more falls and hip fractures.
  • Longer arthroplasty waits and greater deprivation are linked with higher opioid use.
  • The Transitional Pain Service is a Canadian multidisciplinary model running from before surgery to 6 months after discharge.
  • Stratify patients as opioid naive or opioid exposed before arthroplasty.
  • The 2024 UK consensus moves away from numerical pain scores, linear escalation on the WHO ladder and modified-release opioids.
  • Stewardship tools include preoperative tapering, functional pain assessment, multimodal analgesia, prescribing dashboards and standard discharge packs.
  • Procedure-specific discharge prescribing guidance cuts new persistent opioid use.

Jamal N, Clement ND, Duckworth AD, Collinson CV. From surgical backlog to opioid burden. The case for opioid stewardship in arthroplasty pathways. Bone Joint J. 2026;108-B(7):853-8. PubMed

Recent Review. Benzodiazepines and Related Drugs

  • Benzodiazepines bind the GABA-A receptor and raise its affinity for GABA, the main inhibitory neurotransmitter.
  • They increase the frequency of chloride channel opening. Chloride influx hyperpolarises the neuron.
  • The GABA-A receptor is a pentamer. Alpha 1 subunits mediate sedation, alpha 2 and 3 anxiolysis, alpha 5 memory.
  • Z-drugs (zolpidem, zaleplon, eszopiclone) are nonbenzodiazepines acting at GABA-A subunits in the thalamus and hypothalamus.
  • Most skeletal muscle relaxants act centrally at spinal cord, brainstem or cerebrum, with no direct action on muscle.
  • Antispasticity agents (baclofen, tizanidine, dantrolene) treat upper motor neurone spasticity. Antispasmodics treat back pain.
  • Flumazenil is a benzodiazepine antagonist used for reversal and tapering.
  • Benzodiazepines cause dose-dependent respiratory depression, worse with opioids. Opioids feature in 83.5 percent of benzodiazepine overdose deaths.
  • Preoperative benzodiazepine use predicts prolonged opioid use and delirium after orthopaedic surgery (grade B).
  • Benzodiazepines and z-drugs raise hip fracture risk in older people.
More on use and risk
  • Diazepam half-life is 20 to 80 hours. Triazolam is 1.5 to 5.5 hours and zaleplon about 1 hour.
  • Alpha 1, beta 2, gamma 2 is the commonest GABA-A combination in the brain.
  • Dantrolene is also used for malignant hyperthermia.
  • Benzodiazepines lower systemic vascular resistance, with a modest fall in blood pressure and rise in heart rate.
  • Benzodiazepine co-involvement in opioid overdose deaths rose from 8.7 percent in 1999 to 21 percent in 2017.
  • Alprazolam withdrawal may need more than 2 months of tapering.
  • Zolpidem after ACL reconstruction cut narcotic use by 28 percent.
  • Z-drugs can cause ataxia, next-morning impairment and complex sleep behaviours such as sleepwalking.
  • 5.6 to 12 percent of TKA patients took benzodiazepines in the 6 months before surgery.

Hozack BA, Kistler JM, Vaccaro AR, Beredjiklian PK. Benzodiazepines and related drugs in orthopaedics. J Bone Joint Surg Am. 2022;104(24):2204-10. PubMed

Recent Review. GLP-1 Receptor Agonists and Orthopaedic Surgery

  • GLP-1 is an incretin from intestinal L-cells that raises insulin secretion and suppresses glucagon after meals.
  • It reduces appetite peripherally by slowing gastric emptying and centrally through the nucleus of the solitary tract.
  • Human GLP-1 analogues are liraglutide, dulaglutide and semaglutide. Exendin-based agents are exenatide and lixisenatide.
  • Exendin resists breakdown by dipeptidyl peptidase-4, giving a longer half-life.
  • Weight loss of 10 to 15 percent is achievable. Semaglutide 2.4 mg gave 14.9 percent loss at 68 weeks (STEP 1).
  • Delayed gastric emptying raises the risk of aspiration under anaesthesia.
  • ASA advice is to withhold daily doses on the day of surgery and weekly doses for one week before.
  • Gastrointestinal symptoms on the day of elective surgery warrant postponement, full stomach precautions or point-of-care gastric ultrasound.
  • Liraglutide carries a boxed warning for medullary thyroid cancer and MEN 2. Avoid in active pancreatitis or acute kidney injury.
  • Laboratory work suggests GLP-1 agonists stimulate osteoblasts, inhibit osteoclast differentiation and protect chondrocytes from TNF-α oxidative stress.
More on outcomes data
  • Standard fasting is 6 to 8 hours for solids and 2 hours for clear fluids.
  • Rapid weight loss on GLP-1 agonists is linked to cholelithiasis and cholecystitis.
  • LEADER showed a 13 percent reduction in major adverse cardiac events with liraglutide over about 4 years.
  • Database studies link semaglutide before arthroplasty with fewer periprosthetic infections and readmissions.
  • One knee arthroplasty database study also found more acute kidney injury, pneumonia and hypoglycaemia.
  • Bariatric surgery within 6 months before joint replacement is linked to worse outcomes from the catabolic state.

Ramanathan R, Lee JY, Dalton JF, Lin RT, Lee I, Gonzalez C, Shaw JD, Schroeder GD, Kepler CK, Spitnale M, Vaccaro AR, Gabrielli AS, Wawrose RA. GLP-1 receptor agonists in orthopaedic surgery. Implications for perioperative care and outcomes. An orthopaedic surgeon’s perspective. J Bone Joint Surg Am. 2025;107(16):1879-86. PubMed

Reviewed by Professor Phong Tran, Head of Orthopaedic Surgery, Western Health. Last updated 17 October 2026.