Administration of Paracetamol (Acetaminophen) via Rectum for Pain Relief in End-Stage Cancer

John S M Leung^{* *}Correspondence: John S M Leung, Cardiothoracic Surgical Unit, St Paul’s Hospital, Hong Kong, China, Email:

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Introduction

One of the most common and devastating diseases that affects mankind is cancer and by far the most dreaded feature of cancer is not just its lethality but the intractable pain it often inflicts on the patient. In fact, too often the patient suffered so much from pain that death became a welcome relief. Traditionally, the standard of care has been the use of opioid derivatives supplemented with COX inhibitors, preferably the Cyclooxygenase-II (COX II) selective subgroup. As drug tolerance sets in, the dosage has to go up accompanied by rising adverse effects such as respiratory suppression, drowsiness and mental depression, gastrointestinal upset including nausea and vomiting, constipation, hemorrhage and other sufferings. Liver toxicity further adds to deprecation of the patient’s health. Central acting agents like pregabalin or antidepressants might be brought in but they seldom make significant contribution to pain relief. Against such background we seldom think of paracetamol (acetaminophen) one of the commonest analgesics and antipyretics sold over the counter. To begin with, it is usually grouped as one of the unselective COX inhibitors, perhaps somewhat more COX II selective and if much stronger COX II inhibitors like celecoxib and etoricoxib had failed, what chance has a commonplace drug like paracetamol against such formidable pain. In any case, the patient most likely would have obtained it over the counter, tried it at an earlier stage and failed. However, studies have repeatedly shown that paracetamol could be an invaluable component in multimodal pain management (Freo U, 2022).

Literature Review

The route of administration seems to impact on the efficacy of paracetamol as illustrated in the following two cases.

Case illustration 1

A female patient in her mid-50s suffered from extensive local recurrence and multi-organ metastases after hysterectomy and bilateral salpingo-oophorectomy for a high-grade cancer. By the end of two years her condition deteriorated to the extent that patient could not take in any food, drink or medicine by mouth. As patient would only accept a single Peripherally Inserted Central Catheter (PICC), this line was overloaded with total parenteral nutrition along with a host of other drugs to control her unstable blood pressure, fragile hematological condition, bleeding problems and frequent electrolyte imbalances. It appeared desirable to administer some of her medicines by alternate routes as far as possible. Her pain had been controlled to a bearable level with fentanyl patch which had to be progressively increased to the worrisome level of three 50 mcg patches applied simultaneously, along with paracetamol 1 g administered Intravenously (IV) every 4 hours. We decided to change the paracetamol to 500 mg suppository every 8 hours. It seemed to work better than the heavier IV dose and we were able to reduce the fentanyl to two 50 mcg patches, at any one time. The combination of transdermal opioid and paracetamol per rectum managed to keep her pain at a low level until patient went into coma with brain metastasis two months later and died peacefully.

Case illustration 2

A female patient in her early 70s had distal pancreatectomy with splenectomy for ductal adenocarcinoma. Of the 14 regional nodes resected 6 were positive for metastasis. In spite of adjuvant chemotherapy, patient developed early metastasis to the para-aortic nodes and liver. Soon abdominal pain set in, which was unrelieved by an oral combination of tramadol and paracetamol, supplemented with frequent Intramuscular (IM) injections of parecoxib as needed. As patient developed marked nausea and vomiting, her analgesics were changed to one fentanyl 50 mcg patches along with a paracetamol suppository of 250 mg every 8 hours, which was later changed to 500 mg every 12 hours. Parecoxib injection was no longer needed. For the remaining three months of her life, her pain appeared reasonably controlled.

Discussion

Paracetamol is a well-known and commonly used drug. It was considered the active metabolite for phenacetin which rivaled aspirin for relief of pain and fever since the 19^th century but was prohibited a hundred years later due to various toxicities on bone marrow, liver, kidney and carcinogenesis. Paracetamol quickly more than took over the market and became one of the best-selling drugs over the counter. Yet, for such a well-known and widely used drug, knowledge of its properties was very incomplete (Sharma CV and Mehta V, 2014; Athersuch TJ, et al., 2018). In the two cases described, paracetamol had to be given per rectum because the patients ran out of alternate routes of administration. Surprisingly, the rectal route not only worked well, but actually dropped hints that, in spite of being more cumbersome, it might offer certain advantage over the more conventional oral and IV routes. This prompted us to return from bedside to bench and review paracetamol’s pharmacology and biochemical pathways to find an explanation.

Absorption of paracetamol

Although classified as an acid, paracetamol is virtually pH neutral or only marginally on the acidic side of physiological pH. It is not absorbed in the stomach; however, being water soluble, it is rapidly (if not entirely) absorbed in the duodenum. Its spike in blood level after swallowing is sometimes used to measure the gastric emptying time. But the validity of such a gastric emptying time has been challenged (Bartholomé R, 2015). For people with prolonged gastric emptying time such as in chronic gastritis, polypharmacy, debility and terminal cancer the oral absorption and action of paracetamol will be delayed. This problem would have been circumvented by giving the medicine by the rectal route.

Transport and destination of paracetamol

All paracetamol absorbed in the duodenum will drain into the upper part of the portal vein and likely diluted only by the portal venous blood from the stomach, reaching the liver in a relatively higher concentration. Paracetamol absorbed in the rectum will partly drain into the lowest part of the portal system and diluted by the portal venous return of the entire gastro-intestinal tract, reaching the liver with a relatively lower concentration. The other part of the rectal venous drainage goes to the systemic circulation and bypasses the liver altogether. The absorption of paracetamol is subject to spikes due to the arrival of the entire load taken orally, as no part is absorbed during transit through the stomach. During gastric emptying, large amounts of the drug will be loaded into the duodenum. In contrast, absorption from the rectum will be slower and without spikes.

Furthermore, the rectum lacks intestinal villi so that its absorption surface is much smaller than the duodenum virtually ruling out the possibility of creating a paracetamol spike on the liver (Hua S, 2019). The complicated and intriguing mechanism of liver metabolism is such that a big load vs. a small load of paracetamol could make substantial difference in downstream metabolites. With the IV route, such first pass effects do not apply, as paracetamol goes directly to the systemic circulation and only 25% of the drug goes to the liver, of which 2/3 must pass through the gastrointestinal tract first; during this transit, a substantial portion of the drug may diffuse into the intestinal wall or even the intestinal lumen. Only the 5%-8% of cardiac output to the hepatic artery (Rocha FG, 2012) carries the injected drug into the liver with certainty. As shown in the next section only by passing through the liver can paracetamol enter the next step in expediting its major analgesic action.

Metabolism of paracetamol in the liver

In the liver, paracetamol may undergo different processes. It might be conjugated as in a detoxication procedure. It might be converted into a hepatotoxic product accumulation of which may result in liver failure (Athersuch TJ, et al., 2018). It might be converted to an intermediate metabolite which will be further metabolized in the brain to a central acting agent (Bartholomé R, et al., 2015). Some amount of paracetamol will escape liver processing and enter systemic circulation; however, it will not be able to proceed further down the central analgesic pathways.

Conjugation and detoxication

In general, most of the orally taken paracetamol will be detoxified by conjugation, with 50%-70% converted to form paracetamol glucuronide and 25%-35% converted to form paracetamol sulfate. These conjugates are more soluble and readily excreted in the urine and to a lesser extent the bile. But, in large quantity, the excessive paracetamol might need to be detoxicated by Glutathione (GSH), putting some stress on the liver’s antioxidant reserve and increasing the risk of liver damage.

Toxic metabolite

When paracetamol intake increases beyond the safety limit of 4-6 g per day the liver’s capacity of glucuronidation and sulfation would fail to catch up. The excess paracetamol will be converted to the hepatotoxic N-Acetyl-p-Benzoquinone Imine (NAPQI), which requires more GSH for detoxication. As GSH become exhausted, NAPQI levels will increase significantly, closely followed by a corresponding increase of liver damage (Mc Gill MR and Jaeschke H, 2013).

Analgesic intermediate metabolite

The most valuable contribution of the liver in paracetamol analgesic metabolism is the conversion, by deacetylation, of the drug into the active intermediate metabolite, p-aminophenol (4-acetamidophenol) (Högestätt ED, et al., 2005).

This molecule is important because it can be processed by the brain to activate various analgesic pathways. This also explains why paracetamol given through the gastro-intestinal tract whether orally as reviewed by Freo U, 2022.

Rectally, as illustrated in this case, seems to surpass the intravenous (IV) route, which bypasses the liver during its first-pass circulation, in terms of analgesic efficacy.

Metabolism and analgesic activity in the brain

Once the liver-converted paracetamol intermediate metabolite, p-aminophenol, has crossed the blood-brain barrier it exerts two actions. The classical view is that it inhibits COX and exerts antipyretic effect (Flower RJ and Vane JR, 1972).

However, the analgesic action is found to independently follow more complicated pathways. It is first converted by Fatty Acid Amide Hydrolase (FAAH) into the active metabolite N-arachidonoyl-phenolamine (AM-404) (Mallet C, et al., 2023) which activates the Transient Receptor Potential Vanilloid 1 (TRPV1) to expedite central analgesia by modulating several pain pathways especially in the periaqueductal grey (Barriere DA, et al., 2013).

First, downstream of TRPV1, Calcium Voltage-Gated Channel Subunit Alpha 1H (Transient/T Type) (Cav 3.2) is sequentially activated (Francois A, et al., 2013).

Second, TRPV1 channel is also activated, along with the Metabotropic Glutamate Receptor 5 (MGlu5) receptor and the Phospholipase C-Diacylglycerol Lipase-Cannabinoid Receptor Type 1 (PLC-DAGL-CB1) receptor signaling (Barrière DA, et al., 2020).

Third, the bulbospinal serotoninergic receptors, notably 5-Hydroxytryptamine Receptor 7 (5HT7) may be involved through downstream activation (Dogrul A, et al., 2012). Since many of these pathways do not overlap with those of opioids or COX-I/II inhibitors, paracetamol will have an additive or even synergistic effect when combined with these agents, conforming to the popular concept of multimodal analgesia.

Safety of paracetamol

For all its multiple activities, some long established and others newly discovered, the safety of paracetamol is well recognized. Some studies had shown a reduction in blood pressure, particularly among febrile critically ill patients receiving the drug via the IV route (Young TL, 2022). However, in a recent trial, a dose of 4 g daily raised no safety concerns among patients with severe sepsis, even though it failed to yield statistically significant improvement in the final outcome (Ware LB, et al., 2024). Given the unique metabolism of paracetamol in the liver, these studies might not have covered the full range of potential effects and side effects had the drug been administered orally or rectally. This shows the importance of understanding the basic pharmacokinetics of the drug.

Limitations

There have been other studies comparing the results of different routes of paracetamol administrations with different conclusions (Goldstein LH, et al., 2008). They were mainly dealing with post-operative pain among pediatric patients and not entirely applicable to the population of advanced cancer.

The present observations on clinical events limited to one or two cases are anecdotal at best. They will need verification with randomized controlled trials on a statistically valid number of subjects. Such endeavor will need much motivation from both patients and health care providers. Administering a suppository is less convenient than having a tablet. Financial reward for a trial of inexpensive old drug would lack incentive, in stark contrast to the multibillion-dollar stakes of anti-cancer drugs or smartly repackaged opioid preparations. Yet the contribution to humanity in terms of relief of suffering is equally if not more important.

Conclusion

Far from being just another modest COX inhibitor as originally thought, paracetamol has important central acting analgesic properties which seems to place it into a class unique to itself. Such central action depends on its metabolism in the liver to the intermediate metabolite, p-aminophenol. Yet increasing the oral dosage may lead to unacceptable collateral productionof toxic metabolites. It seems that the rectal route of administration could enhance such central acting properties and circumvent some of the problems encountered in the oral route. Pain is one of the most dreaded suffering in cancer and cancer is one of the commonest diseases afflicting mankind. It would seem worthwhile to try almost any method to alleviate cancer pain, especially when such a method is simple, widely available and affordable.

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