Iatrogenic drug withdrawal

"Iatrogenic drug withdrawal" is a topic which clearly belongs in Section 2.1.21 from the second edition of the CICM Syllabus for the Second Part Examination, but which is currently homeless, without a specific syllabus item. It is still highly examinable in spite of that, and Question 6 from the first paper of 2025 had offered an excellent insight into what might be asked about these off-centre pharmacological concepts in the Second part exam. Specifically, the risks factors and epidemiology ("explain why critically ill patients are vulnerable"), assessment ("outline the clinical presentation") and management ("outline the management and prevention") were interrogated. Moisa et al (2025) was the single most useful reference for this topic, and the reader interested in authoritative statements on the subject is redirected there instead.

Definition of iatrogenic drug withdrawal

Iatrogenic drug withdrawal has no consensus definition, but if one had to cludge one together, it could look something like this:

A constellation of signs and symptoms that can be induced by abruptly interrupting or quickly reducing the dose of a drug which the patient was significantly exposed to during their ICU stay.

To be clear: many people (including patients) will experience drug withdrawal in the ICU, but not all such withdrawal is iatrogenic drug withdrawal. The withdrawal from recreational drugs might seem "iatrogenic" because we restrained and intubated the user, preventing them from accessing the agents they are physiologically dependent on, but this is regarded differently for some reason. Those people are discussed under toxicology, not applied pharmacology,  as if opioid molecules glint more evilly through some kind of moral/forensic lens. It is clearly much more understandable and empathy-provoking when it is "withdrawal... of medicines prescribed as part of intensive care management", as asked for in Question 6 from the first paper of 2025. The examiners were testing the candidates for very specific knowledge of the drugs they are usually in charge of. These include:

• Opioids and benzodiazepines, of course
• α2 agonists such as dexmedetomidine and clonidine
• Propofol
• Corticosteroids (insofar as they can be considered "part of intensive care management", because if a respiratory physican recommended it, is it still an intensive care?)
• Antipsychotics
• Nitric oxide
• Antihypertensives

We are not limited to CNS-active agents in this list, but they are the best studied, mostly because most of the data we use is extrapolated from outpatient experience with recreational use and dependence; and there is very little nitric oxide or corticosteroids being sold on the streets.

Epidemiology of iatrogenic drug withdrawal in the ICU

Because there is no definition, the incidence and prevalence of this is very hard to study. This is made even more complicated by the tendency of every author to adopt a new scoring or diagnostic system to describe this (often because they are trying to publish a paper that validates it). Moisa et al (2025) produced a table listing different variations of the diagnostic criteria in the literature (there were about forty). The findings of a prevalence study are obviously going to differ, depending on how you identify this slippery condition. In these papers, the incidence was:

• Opioids: 13.6-49.5%
• Benzodiazepines: 3.2-8.2%
• Propofol: 2.8-17.3%
• Dexmedetomidine: 64% (one study, infusion of >72 hrs)
• Clonidine: 17.5-69.5%

The range is obviously going to be anything between 100%, where you always abruptly stop all your long term infusions without weaning them, to 0%, where you carefully protect the patients from this syndrome.

Risk factors for iatrogenic drug withdrawal in the ICU

Question 6 from the first paper of 2025 asked the candidates to "explain why critically ill patients are vulnerable to IDW", which sounds like a clever way of asking them about the risk factors. There is an excellent table in Moisa et al (2025) that clearly defines this. To paraphrase their table:

• Cumulative dose
• Duration of treatment
• Peak rate
• Weaning rate
• Concomitant use of several agents (classically, opioid + benzo)
• BMI (larger patients = greater risk)
• History of alcohol or drug use prior to ICU admission

But does this really "explain why critically ill patients are vulnerable to IDW"? This could apply to every nonna on the orthopaedic ward. Perhaps a narrative format would be better: 

• Admitted to ICU means severe illness;
• Severe illness means:
  • severe symptoms (pain, distress)
  • therapy which is so intrusive that it would be unendurable without sedation/analgesia
  • prolonged duration of treatment
  • reduced clearance (organ dysfunction)
  • reduced availability of non-tolerance-forming alternatives (eg. NSAIDS are often contraindicated)
• Thus, higher cumulative doses of sedation/analgesia
• Simultaneously, factors that prevent a gentle decremental taper:
  • Time-critical support weaning to prevent deconditioning
  • Need for regular neurological reassessment
  • Unpredictable pharmacokinetics with recovering organ function
• As the result, ICU patients are more at risk of higher cumulative doses and abrupt cessation which precipitates withdrawal
• The diagnosis of withdrawal is then more challenging (it is masked by/blends with delirium of other causes)

Clinical presentation of iatrogenic drug withdrawal

To give a blanket description of this would obviously be impossible, as each drug class has its own clinical withdrawal syndrome. Again, give an excellent breakdown:

• Opioids: rhinorrhea, increased lacrimation, myalgia, diarrhoea, nausea, vomiting, pupillary dilation, insomnia, tachycardia, hypertension, sweating, tachypnea, anxiety, irritability, hyperreflexia, agitation ( from Moisa et al, 2025)
• Benzodiazepines: sleep disturbance, irritability, increased tension and anxiety, panic attacks, hand tremor, sweating, difficulty in concentration, dry wretching and nausea, some weight loss, palpitations, headache, hallucinations,  muscular pain and stiffness (Petursson, 1994, and Arroyo-Novoa et al , 2019)
• α2 agonists: tachycardia, hypertension, agitation, sweating, tremors (Solodiuk et al, 2025)
• Corticosteroids: hyperkalemia, hyponatremia, haemodynamic instability, anorexia, nausea, lethargy, fever, arthralgia, skin desquamation, weakness, postural hypotension, vomiting and weight loss (Dixon & Christy, 1980, and Bhattacharyya et al, 2005)

Complications of iatrogenic drug withdrawal in ICU:

Broadly, all of them:

• Haemodynamic instability (usually in the direction of tachycardia and hypertension)
• Increased agitation (withdrawal posing as delirium)
• Increased oxygen consumption and CO₂ production
• Failure to wean from ventilation (or reintubation)
• Diarrhoea and vomiting leading to feed intolerance (opioids)

Management of iatrogenic drug withdrawal in ICU

There are several possible approaches; Sun & Zhao (2024)  cover this extremely well. It could be separated into logical categories:

• Prevention:
  • Use of modest doses
  • Use of multimodal analgesia/sedation to decrease individual drug doses
  • Early discontinuation and weaning to reduce total cumulative dose
  • Gradual tapering of analgesia and sedation, with a long tail
• Identification of at-risk patients
• Monitoring with withdrawal scales, of which there are several available, eg. the WAT-1 assessment tool, or the Sophia Observation Withdrawal Symptoms Scale (SOS) for paediatric patients
• Amelioration of established withdrawal
  • Same agent reintroduced and then tapered
  • ​​​​​​​Long acting class replacement (eg. oral opioids, methadone)
  • In-class partial agonist replacement (eg. buprenorphine)
  • Out of class replacement (eg. α2 agonists or benzodiazepines to reduce the distress caused by opioid withdrawal, or antipsychotics with sedating activitry for benzodiazepine withdrawal)
• Symptom management
  • ​​​​​​​Lofexidine (for sympathetic effects of opioid withdrawal)
  • Clonidine, anticholinergic antihistamines for diarrhoea and vomiting
  • Antipsychotics for hallucinations and delirium
  • Antiarrhythmics and antihypertensives to prevent adverse cardiovascular consequences of withdrawal-driven sympathetic overactivity