Pholcodine is an opioid anti-tussive (ie. cough suppressant). It is a common component of over-the-counter cough medications. However it has a special significance to anesthesiologists in relation to anaphylaxis risk, particularly related to neuromuscular agents.
Florvaag et al's 2009 review covers this issue very comprehensively. Earlier 2006 research from Florvaag et al attempting to explain some of the regional variability in anaphylaxis rates showed that exposure to pholcodine causes an 60-105 times increase in IgE levels!
Countries where pholcodine use is common (eg Norway) seem to have experienced higher levels of anaphylaxis to neuromuscular blocking agents than countries where it is not common (eg Sweden). In fact, in Norway rocuronium anaphylaxis was such a problem that its use was restricted to modified rapid sequence inductions. A pholcodine containing cough syrup has been withdrawn from the market in Norway because of this (and levels of sensitisation seem to be dropping although it is still too early to draw conclusions). It will be interesting to see if there are other compounds that have a similar effect on IgE sensitisation and whether other countries will consider withdrawing pholcodine products.
In addition to the two articles from Florvaag that specifically look at Pholcodine and it's effects, there is also an interesting review looking at recent insights into anaphylaxis in the anaesthetic setting from Dewachter and team.
Also interesting is Lee et al.'s 2016 case report describing two patients with pholcodine anaphylaxis who then when tested also showed NMBD sensitivity.
Helen Crilly & Michael Rose's 2014 review in Australian Prescriber Anaphylaxis and anaesthesia – can treating a cough kill? is another great summary of the issue.summary
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Sugammadex is pharmacologically great. A modified γ-cyclodextrin Selective Relaxant Binding Agent that reverses rocuronium muscle relaxation 10-times faster than neostigmine (see: Is sugammadex as good as we think?).
At launch, its biggest obvious disadvantage was simply the new drug's high cost. Now as sugammadex has become more widely used, sugammadex-anaphylaxis has risen as a new, prominent concern.
In Japan, where there was a uniquely rapid take-up of sugammadex, it became one of the commonest causes of anaphylaxis. Oriharia (2020) demonstrated an incidence of sugammadex anaphylaxis in Japan of 1 in 5,000 – a risk that most medically communities would consider too high for routine use of a drug with acceptable alternatives.
Given that in some regions (notably Australia & New Zeleand) rocuronium itself has a high-risk of anaphylaxis, the combination of rocuronium-sugammadex may present a greater risk than even old-school drugs such as suxamethonium.
In other countries, such as the United Kingdom, there has not been quite the same incidence of sugammadex-anaphylaxis. Is this simply because of the lower initial use than in Japan, or are there environmental and phenotypical differences as have been implicated for rocuronium anaphylaxis?
Worryingly, if the Japanese experience is representative, then for some locations the combination of rocuronium-sugammadex may in fact have a higher risk of anaphylaxis than using suxamethonium alone.
The true risk of sugammadex-anaphylaxis is still unclear for many populations. However with the looming expiry of the sugammadex patent in 2023, we will see a rapid increase in its use and subsequently reveal any latent anaphylaxis risk.summary
Suxamethonium chloride (suxamethonium, succinylcholine or sux) is a depolarising muscle relaxant that produces rapid-onset, short-duration, deep muscle relaxation. First identified in 1906 and used medically in 1951, it is one of the oldest anaesthesia drugs still widely used. Due to its unique properties and low cost, it remains on the World Health Organisation's List of Essential Medicines
- pH 3.5
- Shelf life 3 years at 4°C, though only 'months' at 20°C.
- Dose - ED95 0.5 mg/kg, IV 1.5 mg/kg, IM 2.5-4 mg/kg.
- Absorption - IM, IV.
- Distribution - >0.2 L/kg; crosses placenta slightly but little effect on foetus.
- Protein binding ?
- Onset 30s IV, 2-3 min IM; Offset 3-5 min.
- Metabolism - PChE to succinylmonocholine (5% activity) & choline -> succinic acid & choline.
- tß½ 5 minutes
- Mechanism - binds to alpha subunit of nicotinic ACh receptor, producing persistent depolarisation (phase 1 & phase 2 blocks).
- CNS - ⇡ intra-ocular pressure (4-8 mmHg rise), ⇡ intra-celebral pressure (to 30 mmHg at 2-4 min).
- CVS - arrhythmias (both bradycardia & tachycardia possible), ⇡ systolic blood pressure, (both negative inotropic and chronotropic effects).
- Resp - 'sux apnoea' pharmacogenetic diversity (94% normal, 3.8% heterozyg (10 min duration of effect), <1% homozog (1-2h duration))
- Renal - hyperkalaemia due to K+ release from muscle; beware in neuromuscular conditions, denervation, and extensive burns.
- GIT - ⇡ intragastric pressure, ⇡ secretions, salivation.
- SEs - anaphylaxis, malignant hyperthermia, sux apnoea, muscle pains, masseter spasm.
An extensive collection of research debunking a range of myths and misconceptions regarding the way we use neuromuscular blocking drugs.
- Myth 1: Modern relaxants are so reliable and predictable that monitoring is unnecessary.
- Myth 2: Post-op residual paralysis is neither common or important.
- Myth 3: Post-op residual paralysis is easy to identify.
- Myth 4: Sugammadex makes residual paralysis a non-issue. (it might, but only if it is routinely available and used!)
- Myth 5: Using propofol and remifentanil we can avoid relaxants for intubation all together.
- Myth 6: Neuromuscular blockade has no effect on BIS.
And bonus myth: deep relaxation is necessary for improving surgical access during laparoscopy.summary
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