Pharmacology of Anaesthetics and Analgesics
In this review essay, we will firstly explore the some background information on the sensation of pain in the human body, followed by looking at the different types of analgesics available for drug treatment. We will then take a closer look at the mechanism of action of paracetamol and non- steroidal anti- inflammatory drugs (NSAIDs), and adverse effects associated with the two types drugs. This will be followed by a comprehensive discussion of the current literature reviews which support that combination therapy of NSAIDs and paracetamol provide better pain relief than single therapy in terms of efficacy and safety. Finally the essay will conclude with addressing a few limitations that is present in the studies.
Pain is defined as an unpleasant feeling as a result of a stimulus (Principles of neural science / edited by Eric R. Kandel, James H. Schwartz, Thomas M. Jessell , 1991). In the human body pain can originate from different localised regions of the body, this can be broadly categorised into three categories: visceral pain which originates from the smooth muscle, visceral pain is often hard to localise, somatic pain which originates from skeletal muscle, ligaments, and joints, somatic pain is often easier to localise in comparison to visceral pain. The last source of pain is neuropathic which involves pain originating from the peripheral and central nervous system (Principles of neural science / edited by Eric R. Kandel, James H. Schwartz, Thomas M. Jessell , 1991).
The sensation of pain should receive prompt medical attention; analgesics are a broad class of drugs which will help relieve pain (Eija & Kalso, 2009). Analgesics can be categorised as opioids, non- opioids, and adjuvants. According to the World Health Organisation (WHO), administration of analgesic drugs should follow the 'pain ladder' model to achieve cost- effective and effective pain management (Organisation, 2012). In the 'pain ladder' model pain is categorised as mild, moderate and severe. For mild pain administration of paracetamol should be sufficient to give pain relief, moderate pain requires paracetamol coupled with a mild opioid drug or ibuprofen, and for severe pain paracetamol coupled with a stronger opioid or ibuprofen. This model has been clinically proven to be effective 80 to 90% cases (Organisation, 2012).
In this review focus will be placed on paracetamol and NSAIDs, both drugs are non-opioid drugs (Bisgaard, 2006). Both drugs are commonly used in clinical practice for postoperative pain management; the two drugs have different mechanism of action. The general mechanism of action behind NSAIDs is that they inhibit cyclooxygenase enzyme, thus inhibiting the production of prostaglandins (Raffa, 2001). The administration of NSAIDs comes with its side effects, most of the side effects results from the reduction in prostaglandin production. Side effects primarily involve gastrointestinal bleeding or ulceration, reduced ability for platelet aggregation and nephrotoxicity (Raffa, 2001). In comparison to NSAIDs, paracetamol is considered to be a safer therapeutic drug as it does not inhibit prostaglandin production to a significant degree. It has been shown that overdose of paracetamol is associated with hepatotoxicity. As long as the daily dose is below 4 grams per day there should be no risk of hepatotoxicity unless the patient has conditions which predisposes them to hepatotoxicity even at safe dosages (Raffa, 2001). The mechanism of action of paracetamol is still debated, it has been suggested that paracetamol may act of the COX pathway and reduce prostaglandin production levels (Anderson, 2008). Despite paracetamol having lesser adverse effects in comparison to NSAIDs, some studies have shown NSAID is more superior than paracetamol in terms of pain management (Bisgaard, 2006).
It has been shown that there are patients that are not able to relieve pain postoperatively even if they follow the standard analgesic administration as instructed by the medical professional (Elvir-Lazo & White, 2010). This coupled with the increase in outpatient population, due to the medical advances which allow patients to receive the same quality outcome even if they are not at the hospital. With the increase in outpatient population there is an increasing demand for the development of multimodal drug regimens which are effective, inexpensive, intrinsically safe and easily managed by the patient or their family members (Elvir-Lazo & White, 2010). For this reason it has been suggested that perhaps by co- administering drugs that will act in a synergistic manner, would reduce the dosage required, increase efficacy and reduce the adverse effects experienced by the patient (Hyllested, Jones, Pedersen, & Kehlet, 2002). Developing an efficient multimodal drug regimen is important; however there are also other factors that need to be addressed in order to improve postoperative pain management. These include patient compliance with treatment and enhancing communication between patients and medical professionals after the surgical procedure (Elvir-Lazo & White, 2010).
A commonly used combination of drugs administrated to patients that undergo various surgical processes, is the co- administration of NSAIDs and paracetamol. In a study it showed that as NSAIDs and paracetamol had to be taken at different time intervals, this made it difficult for some patients to comply with the treatment (Hyllested et al., 2002). This suggested that the manufacturing of one tablet which contains both paracetamol and NSAIDs would result in higher patient compliance, thus better pain management outcomes. A study which evaluated the effectiveness of maxigesic (combination of ibuprofen and paracetamol) showed more superior analgesic outcomes in comparison to taking ibuprofen and paracetamol as two separate tablets at different times of the day (Hyllested et al., 2002).
Different studies have been performed to analyse the efficacy of multimodal analgesic treatment in comparison to unimodal analgesic treatment. In a study performed by Bisgaard group, they analysed randomized control trials with regards to pain management after laparoscopic cholecystectomy (Bisgaard, 2006). The conclusions drawn from the study are representable as it did exclude studies which had poor methodological design. The conclusion reached was that out of the 64 studies analysed, majority of the studies showed that the administration of ketoprofen shortly prior to or during the surgical procedure followed by co- administration of both drugs for 3 to 4 days following the procedure showed the most effective pain management outcomes. This conclusion does however have its limitations, as the studies that analysed postoperative pain management could have a better methodological design that takes into account variation in the level of pain experienced by patients after the surgical procedure (Bisgaard, 2006). Also there was no placebo control group for comparison with the patient group that received multimodal analgesics. However, it can be argued that a placebo group is not necessary, both this study and another study performed by Merry et al. states that there has been previous studies which documents the efficacy of combination therapy of NSAIDs and paracetamol in comparison to a placebo group, and also in the including a placebo group in the studies could be considered to be unethical (Merry et al., 2010). Despite the limitations of this study, we can still have reasonable confidence in the results that multimodal analgesics involving ketoprofen and paracetamol is effective for postoperative pain management.
To further evaluate the efficacy of combination therapy, a more concise qualitative analysis was done on studies performed between 1966 to January 2001 on Medline. The analysis evaluated each study for its methodological design, the criteria to be included was to have a randomised control trial which was double blinded, with humans as subjects and had to have a minimal single dose of paracetamol at 1000 mg unless the study involved children or the paracetamol was co- administered with another type of drug (Hyllested et al., 2002). This methodology for selecting which studies are included in the study was repeated again by a study performed by Ong et al. in 2010, which emphasizes that this selection method is reliable (Ong, Seymour, Lirk, & Merry, 2010). The study demonstrated that different surgical procedures cannot be compared with one another, so the results were stratified based on the different surgical procedures performed to improve the reliability of the results (Hyllested et al., 2002). In the study it showed that majority of studies showed that NSAIDs is more superior in comparison to paracetamol alone. Some studies suggested that paracetamol does not play a significant role in combination therapy, and it is mostly NSAIDs that contribute to pain relief. This theory has been rebutted by studies that have performed comparison of NSAIDs and paracetamol versus NSAIDs alone, although there haven't been a lot of studies performed on this. All of the studies that did test this showed consistent findings that paracetamol does enhance analgesic efficacy when co- administered with NSAIDs (Hyllested et al., 2002). Although the study included data from various different studies, a definitive conclusion still cannot be reached with regards to combination therapy of NSAIDs and paracetamol being more the more superior in comparison to administering NSAIDs or paracetamol alone.
The study performed by Hyllested et al. was repeated again by Ong et al. in 2010, where the literature search included Medline, Embase, and Cumulative Index to nursing and allied heath literature, and pubmed. This study performed included papers published up to June 2009 (Ong et al., 2010). We would expect this publication to contain some new insights into the efficacy and safety issues with regards to combination therapy using NSAIDs and paracetamol. In comparison to the study performed by Hyllested et al. this study stratified the studies based on the mode of administration of the drugs and surgical procedures, whereas Hyllested et al. only stratified the studies based on the surgical procedure performed. However in this study the pain intensity results from different surgical procedures was combined together. Another aspect in this study is that a more accurate method of representing pain intensity was used. In the Hyllested et al. study there was one study that was included which used an insensitive 4 point pain scale, which generated results that could not differentiate the differences between perceived pain after administration of NSAIDs in comparison to paracetamol (Hyllested et al., 2002). The results shown from the study by Ong et al. was consistent with the findings by Hyllested et al, combination therapy of NSAIDs and paracetamol generates more effective pain relief in comparison to single drug therapy (Hyllested et al., 2002; Ong et al., 2010).
The evaluation of efficacy of multimodal analgesic treatment in comparison to unimodal analgesic treatment is important; however the number of adverse effects experienced in multimodal analgesic treatment also needs to be evaluated. It has been found through various studies performed that there is no evidence of increased incidence in the adverse effects associated with combination therapy in comparison to single drug therapy (Hyllested et al., 2002; Merry et al., 2010; Ong et al., 2010). Those findings are also consistent with one study that followed patients for 3 weeks after their oral surgery, showed the group which received ibuprofen alone showed the least number of adverse effects . However the group which received both ibuprofen and paracetamol did not show adverse effects which were are of clinical significance over the three week period, therefore it is reasonable to conclude that the combination therapy is safe to use considering it does also provide better pain relief after the surgery. The study only consisted of 40 participants in each group; this number is too small to reach a conclusive statement. A study with a larger participant pool would be required to provide conclusions with more confidence. As the study did follow the participants for a 3 week period, it would be unlikely that any clinically relevant adverse effects experienced by the patient as a result of the analgesic drugs would have been missed, it wouldn't be necessary to extend the follow up period as the results would be reliable due to decreasing compliance over time as patients in general will stop taking the drugs as the pain eases.
Many studies also reported that there was higher incidence of adverse effects experienced in patients that received single drug therapy. This was mainly attributed to the single drug was not able to give adequate pain relief therefore a supplementary dose (Merry et al., 2010Merry et al., 2010)of morphine was administered. This increased the incidence of nausea and vomiting reported with patients that received a single drug therapy.
However despite the large portion of the studies that shows that combinational therapy does increase efficacy without increasing adverse effects. This does not mean combination therapy should replace single drug therapy. There are times where the patient condition will only require one drug and not the other, thus giving them a combination drug therapy will expose the patients to unnecessary adverse effects. The administration of paracetamol and NSAIDs should be evaluated carefully on a case to case basis.
A limitation in the study performed by Hyllested et al. is that the study was a qualitative review as oppose to a quantitative review. This is the same limitation seen in the study performed by Cliff et al. However both studies have stated that this is due to the heterogeneity in the study design makes it impossible to carry out a quantitative analysis. Also in the study performed by Cliff et al, a wide range of acute pain models were included in the study, and the results were combined to generate the funnel plots, this has been criticized by other academics. This is arguable as although most studies have separated the results are categorised based on the type of surgical procedure performed, there has been two systematic review papers that show suggest there is minimal differences in the acute pain intensity between the different surgical procedures.
In conclusion, from the studies that have been analysed there is strong evidence which suggests that effective multimodal analgesic treatment is necessary with the expansion of outpatient population. By coupling two drugs which have synergistic effects does show enhanced postoperative pain relief in comparison to unimodal analgesic treatment. Numerous studies have been performed on the efficacy of combining NSAIDs and paracetamol for enhanced pain relief. Although none of the studies show definitive results due to methodological design, individual biodiversity, sources of bias, random error, and other limiting factors prevents establishment of a definitive conclusion. However, from the large proportion of studies which show consistent results that combination therapy is more effective in comparison to single drug therapy, it is reasonable to conclude that combination therapy is more effective for giving better pain relief.
Hyllested, M., Jones, S., Pedersen, J., & Kehlet, H. (2002). Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review. British journal of anaesthesia, 88(2), 199-214.
Merry, A., Gibbs, R., Edwards, J., Ting, G., Frampton, C., Davies, E., & Anderson, B. (2010). Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults: a randomized controlled trial. British journal of anaesthesia, 104(1), 80-88.
Ong, C. K. S., Seymour, R. A., Lirk, P., & Merry, A. F. (2010). Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesthesia & Analgesia, 110(4), 1170-1179.