Description of the condition

Cancer is estimated to cause over eight million deaths per annum ‐ approximately 13% of deaths worldwide (IARC 2012). Globally, 32 million people are living with cancer, and detailed information for individual countries is available on the WHO website for the International Agency for Research on Cancer (http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx). In the UK alone in 2014, there were around 350,000 new cases of cancer annually, with around 50% of people surviving for 10 years or more after diagnosis (Cancer Research UK 2016).

Cancer pain is perhaps one of the most feared symptoms associated with the disease. Pain may be the first symptom to cause someone to seek medical advice that leads to a diagnosis of cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain (Portenoy 1999). Pain can occur at any time as the disease progresses, but the frequency and intensity of pain tends to increase as the cancer advances (Portenoy 1999; Van den Beuken‐van Everdingen 2016). For people with advanced cancer, some 75% to 90% will experience pain having a major impact on daily living (Wiffen 2016). Pain had a significant negative correlation with quality of life in people with cancer in China, Japan, and Palestine, for example (Deng 2012; Dreidi 2016; Mikan 2016). A recent systematic review has shown that approximately 40% of patients suffered pain after curative treatment, 55% during cancer treatment and 66% in advanced disease. Pain related to cancer is frequently described as distressing or intolerable by more than one‐third of patients (Breivik 2009; Van den Beuken‐van Everdingen 2016).

Cancer pain can be the result of the cancer itself, interventions to treat the cancer, and sometimes other underlying pains. Prevalence of pain is also linked to cancer type, with head and neck cancer showing the highest prevalence. Age also has an impact, with younger patients experiencing more pain (Prommer 2015). For this review, we will not consider postsurgical pain related to surgery or neuropathic pain related specifically to chemotherapy or nerve pressure.

The current World Health Organisation (WHO) cancer pain ladder for adults recommends the use of non‐opioid analgesics, including paracetamol, as the first step on the ladder, with or without an adjuvant (WHO 2016). Non‐opioid analgesics are also to be used on the second and third steps, together with weak or strong opioids. The current National Institute for Health and Care Excellence (NICE) in the UK advises that non‐opioid analgesics alone be used for treating mild pain (0 to 3 on a 0 to 10 pain scale), together with a weak opioid or such as codeine or tramadol for mild to moderate pain (3 to 6), and with a strong opioid such as morphine for severe pain (6 to 10) (NICE 2016). Some authorities have suggested that the second step on the ladder could be removed, and replaced with low doses of strong opioids such as morphine (Twycross 2014).

Children with cancer consider pain as the most prevalent symptom, usually resulting from treatment side effects or painful procedures (Twycross 2015). The amount and quality of research on pharmacological treatments for children tends to be poor (Mercadante 2014).

Description of the intervention

Paracetamol (acetaminophen) is available in a very large number of formats and products with different names, including Panadol and Tylenol. Paracetamol plus codeine often comes with the generic name co‐codamol, and paracetamol plus dihydrocodeine as co‐dydramol. A listing of brand names by country is available but the list is too long to be given here (Drugs.com 2016). Paracetamol use is measured in thousands of tonnes, and questions have been asked about the benefits and risk of such extensive use (Moore 2016).

Paracetamol was first identified as the active metabolite of two older antipyretic drugs, acetanilide and phenacetin, in the late nineteenth century (Axelrod 2003). Since then, it has become one of the most popular antipyretic and analgesic drugs worldwide, and is often also used in combination with other drugs. It became available in the UK on prescription in 1956, and without prescription (over‐the‐counter) in 1963 (PIC 2015). Nonprescription medications are less expensive, more accessible, and have favourable safety profiles relative to many prescription treatments. There have been calls for the position of paracetamol as a widely‐available analgesic to be re‐evaluated, based on an assessment of evidence over the past 130 years (Brune 2015).

Despite a low incidence of adverse effects, paracetamol has a recognised potential for hepatotoxicity and is thought to be responsible for approximately half of all cases of liver failure in the UK (Hawton 2001), and about 40% in the US (Norris 2008). One study, evaluating all cases of acute liver failure leading to registration for transplantation (ALFT) across seven European countries for a three‐year period, showed that paracetamol overdose was responsible for one‐sixth of cases of ALFT, though this varied considerably between each country (Gulmez 2015). Acute paracetamol hepatotoxicity at therapeutic doses has been judged to be extremely unlikely, despite reports of so‐called 'therapeutic misadventure' (Prescott 2000). However, it has been observed that non‐overdose ALFT is more likely to follow therapeutic‐dose paracetamol exposure than similar NSAID exposure (Gulmez 2013). Legislative changes have been introduced in the UK to restrict pack sizes and the maximum number of tablets permitted in nonprescription sales (CSM 1997) on the basis of evidence that poisoning is lower in countries that restrict availability (Gunnell 1997; Hawton 2001). The contribution of these changes, which were inconvenient and costly (particularly to people with chronic pain), to any observed reductions in incidence of liver failure or death, remains uncertain (Bateman 2014a; Bateman 2014b; Hawkins 2007; Hawton 2013). Changes have also been made in the USA, and professionals have been advised not to dispense prescription combination drugs with more than 325 mg paracetamol.

There is a substantial public health impact of paracetamol toxicity. In the USA, incidence proportions peaked at age two years and ages 16 to 18 years (Altyar 2015). There have been concerns over the safety of paracetamol in people with compromised hepatic function (people with severe alcoholism, cirrhosis, or hepatitis), but these have not been substantiated (Dart 2000; PIC 2015).

The use of paracetamol during pregnancy has been questioned following reports that it is linked to behavioural problems and hyperkinetic disorders in children whose mothers took it during pregnancy (Liew 2014), and suggestions that it can interfere with sex hormones (Mazaud‐Guittot 2013).

In an analysis of single‐dose studies in migraine, there was no evidence that adverse events were more common with paracetamol 1000 mg than with placebo, and no serious adverse events occurred with paracetamol alone (Derry 2013b).

Oral paracetamol has long been used as a first‐line analgesic for a variety of acute and chronic conditions. It has modest efficacy in acute pain and migraine (Derry 2013b; Toms 2008), although some randomised trials, systematic reviews, and meta‐analyses have suggested that there is no good evidence for a clinically relevant benefit of paracetamol (as monotherapy) in many chronic pain conditions, such as osteoarthritis and back pain (Machado 2015; Moore 2014a; Williams 2014). There are few or no data for a range of other common painful conditions, including dysmenorrhoea and neck pain. Moreover, accumulating evidence from observational studies indicates a considerable degree of paracetamol toxicity, especially at the upper end of standard analgesic doses (Roberts 2016).

How the intervention might work

The lack of significant anti‐inflammatory activity of paracetamol implies a mode of action distinct from that of NSAIDs; yet, despite years of use and research, the mechanisms of action of paracetamol are not fully understood. NSAIDs act by inhibiting the activity of cyclo‐oxygenase (COX), now recognised to consist of two isoforms (COX‐1 and COX‐2), which catalyses the production of prostaglandins responsible for pain and inflammation. Paracetamol has previously been shown to have no significant effects on COX‐1 or COX‐2 (Schwab 2003), but is now being considered as a selective COX‐2 inhibitor (Hinz 2008). Significant paracetamol‐induced inhibition of prostaglandin production has been demonstrated in tissues in the brain, spleen, and lung (Botting 2000; Flower 1972). A 'COX‐3 hypothesis', wherein the efficacy of paracetamol is attributed to its specific inhibition of a third COX isoform enzyme, COX‐3 (Botting 2000; Chandrasekharan 2002), now has little credibility, and a central mode action of paracetamol is thought to be likely (Graham 2005). Paracetamol metabolism is subject to genetic variation (Zhao 2011).

There is some experimental research in rats to suggest that paracetamol may have an effect in neuropathic pain via cannabinoid receptors (Curros‐Criado 2009; Dani 2007). One single case report suggested intravenous paracetamol was effective for phantom limb pain (Gulcu 2007).

Why it is important to do this review

A previous Cochrane review examined the evidence for NSAIDs or paracetamol, alone or combined with opioids, for cancer pain (McNicol 2015), with the last search date in 2005. There have been few subsequent systematic reviews of the evidence. Nabal (Nabal 2011) examined the evidence for combinations with opioids, finding little evidence. A review of paracetamol and NSAIDs concluded that while the role of these non‐opioid drugs remains controversial, the evidence for paracetamol alone was limited (Mercadante 2013).

The evidence of effectiveness of the WHO pain ladder for cancer has been examined several times in the past two decades. These studies reported varying degrees of success, typically between 20% and 100% of people with cancer pain achieving good relief (Azevedo São Leão Ferreira 2006; Carlson 2016; Jadad 1995), with some suggesting that as many as 50% of people with cancer pain are undertreated (Deandrea 2008).

In many countries, opioids are severely restricted, if available at all. This leaves many people with cancer at the risk of severe life‐limiting pain unless non‐opioid analgesics can be used. This review will inform policy makers such as the WHO on the possible utility of paracetamol to treat cancer‐related pain. It is hoped that the review will inform patients and carers on the value or otherwise of paracetamol in this context.

Other relevant Cochrane reviews include an assessment of codeine alone and with paracetamol (Straube 2014), and an evaluation of tramadol alone and with paracetamol (Wiffen 2017). A number of other reviews have evaluated the evidence for opioids, including buprenorphine (Schmidt‐Hansen 2015a), transdermal fentanyl (Hadley 2013), hydromorphone (Bao 2016), morphine (Wiffen 2016), oxycodone (Schmidt‐Hansen 2015b), and tapentadol (Wiffen 2015).

The standards used to assess evidence in pain trials have changed substantially in recent years, with particular attention being paid to trial duration, withdrawals, and statistical imputation following withdrawal, all of which can substantially alter estimates of efficacy (Moore 2014b). The most important change is the move away from using mean pain scores, or mean change in pain scores, to the number of people who have a large decrease in pain (by at least 50%) (Dworkin 2008; Moore 2013a). Pain intensity reduction of 50% or more correlates with improvements in comorbid symptoms, function, and quality of life generally (Moore 2013b). These standards are set out in the PaPaS author and referee guidance for pain studies of the Cochrane Pain, Palliative and Supportive Care Group (PaPaS 2012).

Three additional issues potentially affect how evidence is evaluated.

The first issue is study size and the overall amount of information available for analysis. There are issues over both random chance effects with small amounts of data, and potential bias in small studies, especially in pain (Dechartes 2013; Dechartres 2014; Fanelli 2017; Moore 1998; Nguyen 2017; Nüesch 2010; Thorlund 2011). Cochrane reviews have been criticised for perhaps overemphasising results of underpowered studies or analyses (AlBalawi 2013; Turner 2013). On the other hand, it may be unethical to ignore potentially important information from small studies or to randomise more participants if a meta‐analysis including small, existing studies provided conclusive evidence. In this review, we have therefore chosen to limit analyses to studies with a minimum of 25 participants randomised per treatment group, which we believe has not been done previously.

The second issue is that of study duration. Previous reviews have examined studies of any duration, even in some cases single‐dose studies, or studies lasting one day or less, often with intravenous or intramuscular formulations (McNicol 2015; Mercadante 2013). While short term studies and non‐oral formulations may have some relevance in some circumstances, they have little relevance to the vast majority of people with cancer pain who will be treated with oral paracetamol over weeks, months, or even years. We have therefore chosen to include only studies with five days' duration or longer.

The third issue is that of comparators. Many cancer pain studies involve direct comparisons of one or more formulations of the same drug, as particularly noted for oral morphine (Wiffen 2016). This type of design has limited importance in evaluating the analgesic contribution of a drug, if that is not already well established (McQuay 2005). For that reason, we have limited this review to the two comparators that speak to the efficacy of paracetamol in cancer pain, namely the comparison of paracetamol versus placebo, and paracetamol plus opioid versus the same dose of opioid alone. The latter comparison would be similar to methods used for determining dose‐response of analgesics in acute pain (McQuay 2007), or caffeine as an analgesic adjuvant in acute pain (Derry 2014).