Dr Adam Woo
Research Pain Fellow, UCL Hospitals
Paracetamol is one of the more ubiquitous drugs in hospital and community settings. Although widely used, its actions are still not fully elucidated. With the relative recent availability of an intravenous solution, its use is revitalised, especially in the perioperative setting. This article explores the intravenous form of the drug looking at some basic science as well as evidence for its efficacy in clinical practice and mechanisms of action.
Why give it as a solution?
A solution of paracetamol simply means that it can be given intravenously. The easiest and cheapest method of administration is oral but that is not an option intraoperatively or in some patients with bowel obstruction, for example. The rectal form of administration is unreliable and erratic. It gives a very variable peak plasma concentration, which is also reached later, at 2 to 3 hours. As with most drugs, intravenous administration is more reliable and reaches peak concentrations faster compared with oral routes, as proven for paracetamol . Paracetamol has a different mechanism of action compared with usual analgesics like opiates and non-steroidal anti-inflammatory drugs, which have considerable adverse effects. Since paracetamol’s side effect profile is considerably superior, availability of an intravenous form is very useful when other routes are less feasible.
The active ingredient is not considered water soluble at 1.43 g/100 cm3 in cold water. This solubility increases at higher temperatures. Hydrophilic ingredients in Perfalgan like mannitol and disodium phosphate make it soluble. Hydrolysis is controlled by a pH buffer of sodium hydroxide and disodium phosphate. Oxidation is prevented by adding cysteine hydrochloride and an oxygen free manufacturing process.
Was there a predecessor for iv paracetamol?
Yes - propacetamol. Propacetamol is a prodrug and is a diethylglycidyl ester of paracetamol. It is more water soluble than paracetamol and is rapidly cleaved to paracetamol and diethylglycine by esterases when given parenterally. Propacetamol seems to be more allergenic than paracetamol as N,N-diethylglycine causes sensitisation in the human skin . Propacetamol is also much more expensive than paracetamol tablets or intravenous paracetamol, partly because it needs to be reconstituted in sodium citrate.
The time course of action is quick with iv paracetamol as it reaches peak concentration as soon as infusion is complete (about 15 minutes). According to the product information, the analgesic effect starts within 5 minutes, peaks at 1 hour and lasts 4 to 6 hours. This is consistent with a plasma half-life of 2.7 hours - i.e. about two half-lifes. The antipyrexial activity lasts 6 hours.
This time course can be altered. If the speed of infusion is slowed down, then the onset and time to peak effect will be prolonged. If the patient is very heavy or large, the peak effect may be decreased (higher Vd and hence lower peak plasma levels). In liver failure, the metabolism may reduced, prolonging paracetamol action. In people taking enzyme-inducing agents or alcohol the metabolism of paracetamol may increase, hastening the decrease in paracetamol levels in plasma. Since the elimination is through the kidneys, patients in renal failure may take more time to clear paracetamol from the body. However, only less than 5% of given paracetamol is excreted unchanged, and its metabolites (also excreted through the kidneys) are inactive. Probenecid tends to increase plasma levels of paracetamol . In the very young, metabolism and elimination take longer.
How does this compare to propacetamol?
The bioavailability of 500 mg of perfalgan is equivalent to 1 g of propacetamol, as determined by the area under the curve of paracetamol levels over time. This was compared in 1 g paracetamol vs 2 g propacetamol  after a washout period of a week between drugs. Presumably, 1 g of propacetamol is hydrolysed to the equivalent of 500 mg of paracetamol once in the circulation.
The primary metabolic pathway for paracetamol is glucuronidation in the liver and, to a much lesser extent, sulphation, both of which are non-toxic. A small amount of the drug is metabolised via the cytochrome P-450 pathway (specifically CYP1A2 and CYP2E1, and to a lesser extent CYP2D6) into N-acetyl-p-benzoquinone-imine (NAPQI), which is extremely toxic to liver tissue, as well as being a strong biochemical oxidiser. Genetic polymorphism of the Cyt-P450 gene may render those ‘rapid’ metabolisers more prone to NAPQI production .
The small amount (approximately 5-8% of paracetamol dose) of NAPQI that is produced is immediately inactivated by conjugation with glutathione.
Is it useful for analgesia? What is the evidence?
Yes, perfalgan is useful for treating acute pain. The Product Information sheet provides quite convincing evidence for analgesia in postoperative orthopaedic surgery and for oral surgery.
There are, however, many more studies.
Paracetamol is opioid sparing. In one study performed after surgery for removal of impacted third molar teeth, propacetamol administered intravenously in repeated doses had a significant analgesic effect indistinguishable from that of intramuscular morphine but with an improved side effects profile . Intravenous propacetamol has been shown to reduce PCA morphine requirements after spinal surgery  and hip arthroplasty . We assume here that propacetamol would act in the same manner as Perfalgan.
More recently, a randomised, double-blind, placebo-controlled trial showed that 2 g of intravenous paracetamol provides better pain relief than 1 g i.v. administration, with seemingly no difference in side effect profiles . This should be investigated further to assess plasma levels vis-à-vis clinical analgesia.
Perfalgan should be considered only if enteral routes are not available and also not used as a substitute for opioids in severe pain. Intravenous doses must be clearly recorded when given perioperatively as oral paracetamol preparations are readily given in the postoperative period as well.
In children less than 6 months of age, limited studies are available, In the PI, the half-life of paracetamol for neonates is longer, at 3.5 hours. Other than that, the safety and efficacy is not known. In a case study, a neonate was given a massive dose (136 mg/kg) and yet there were no long-term sequalae nor evidence of hepatic damage . Although this was an oral dose, the intravenous safety can be extrapolated and gives an indication of its high therapeutic index. As a safety measure, 100 ml Perfalgan bottles should not be stored on paediatric wards.
Children older than 6 months of age have similar pharmacokinetic profiles to adults, in addition to a very good safety profile.
In those with renal failure, the glucuronide and sulphate metabolites will accumulate, although they are non-toxic and are therefore generally safe to use. Reports of renal failure following paracetamol toxicity are rare but well known, hence proper hydration of a patient must be observed before administration.
Since it is metabolised in the liver, any form of liver impairment would necessitate cautious administration. In addition, those on enzyme-inducing agents like phenytoin, alcohol or rifampicin may produce more toxic metabolites via the cytochrome p 450 route. People with chronic malnutrition and also some alcohol abusers have low reserves of glutathione to counteract the N-acetyl-p-benzoquinone-imine produced. Having said that, patients with hepatitis C treated with interferons, or even those with liver cirrhosis, seem to tolerate paracetamol well, if normal doses are adhered to .
Precautions in patients with a higher risk of suicide or self-harm should be exercised, especially if administered for long-term use. Of course, paracetamol is an over-the-counter drug, which is easily available anyway. In the UK, sales of over-the-counter paracetamol are restricted to packs of 32 tablets in pharmacies, and 16 tablets in non-pharmacy outlets .
Repeated dosing of intravenous paracetamol has not been studied, and long-term regular intravenous therapy should be avoided
Side effects of intravenous paracetamol are classified as ‘rare’ in the BNF; they include rashes, blood disorders and hypotension on infusion . Of course, overdose is the most problematic side effect. Given the rarity of side effects, they are not problematic. Compared with many standard analgesics, paracetamol is really very safe and is also versatile, in that it has been used in all age groups. The reaction at infusion site seen with propacetamol is not generally a problem with Perfalgan.
Mechanism of action
The precise mechanism of action of paracetamol is not fully clear. It has always been thought to have a strong central action, supported by the fact that paracetamol is found in significant concentrations in the CSF after infusions in adults and in children .
Prostaglandin synthesis relies on the action of cyclooxygenase (Cox) enzymes on arachidonic acid. For this to occur, cyclooxygenase must be in an oxidised form. Paracetamol seems to reduce this oxidised form, rendering the enzyme less effective . Reduced prostaglandin synthesis in this manner may explain analgesia. The other family of Cox enzymes, Cox 3, was thought to mediate analgesia in humans  but this theory has now lost favour, as Cox 3 is not thought to be active in humans .
Paracetamol is also thought to affect the endogenous cannabinoid system. Paracetamol is metabolised to AM404, also known as N-arachidonoylphenolamine . This compound prevents the reuptake of endogenous cannabinoids like anandamide from the synaptic cleft. Since blockade of cannabinoid type 1 (CB1) receptors attenuate the action of paracetamol , this theory is gaining credibility. AM404 is also a TPRV1 agonist, which is also activated by the analgesic drug capsaicin. Paracetamol may act along the same lines.
Cox, TPRV1 and cannabinoids in combination could be involved not only in pain, but also thermoregulatory pathways .
Another candidate for the action of paracetamol is the 5-HT3 receptor. A 5-HT3 antagonist was found to block the antinociceptive action of intrathecal paracetamol , supporting this notion.
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