Medicines Q&As. Medicines Q&As. What is the evidence to support the use of IV paracetamol for the treatment of pain? Background.

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Medicines Q&As Q&A 361.1 What is the evidence to support the use of IV paracetamol for the treatment of pain? Background Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Date prepared: August 2010 Intravenous (IV) paracetamol is licensed for the short-term treatment of moderate pain, especially following surgery and for the short-term treatment of fever. Use of the IV route is clinically justified by an urgent need to treat pain or hyperthermia and/or when other routes of administration are not possible (1). There is however concern that the IV route may not always be chosen appropriately, due to! associated risks of infection or local pain and inflammation! potential for overdose with concomitant orally administered medicines containing paracetamol or in patients with hepatic impairment or severe renal impairment! failure to adjust the dose according to body weight or other patient-related factors! increased nursing time and costs. Answer For some years paracetamol for IV use was only available (not licensed in the UK) in the form of propacetamol, a pro-drug of paracetamol. A dose of 2g of propacetamol is hydrolyzed to 1g of paracetamol (2) within 7 minutes of administration. Bioequivalence (3) and therapeutic equivalence (4) of 2g of IV propacetamol and 1g of IV paracetamol have been demonstrated. A large proportion of the efficacy data on IV paracetamol is derived from studies of IV propacetamol. Post-operative pain! Pharmacokinetics IV vs Oral The manufacturer of IV paracetamol recommends the use of a suitable analgesic oral treatment as soon as this administration route is possible (1). There may be situations where this is not appropriate e.g. following abdominal or gastric surgery where normal stomach motility may not be restored for 15 hours or more, also after oral surgery, or if a rapid onset of action is required (5). Paracetamol is not absorbed in the stomach, therefore delays in gastric emptying decrease the transfer of drug to the small intestine, resulting in diminished peak plasma concentrations (6). A one-off dose of IV paracetamol in the immediate post-operative period has been suggested to achieve baseline analgesia in the sedated patient (5). The onset of analgesia occurs rapidly within 5-10 minutes of IV paracetamol administration. The peak analgesic effect is obtained in 1 hour and its duration is approximately 4-6 hours (1,4). Although oral bioavailability is good (63-89%), early plasma concentrations following oral administration may vary, and in some cases may remain subtherapeutic (7). The minimum plasma paracetamol level required for analgesia and antipyresis is thought to be 10 mcg/ml (66 micromol/l) and although not clearly defined, the therapeutic range is usually considered to be 10-20 mcg/ml (66-132 micromol/l) (8). In a small study comparing early bioavailability of paracetamol after oral or IV administration, 35 adult patients undergoing day surgery (5 groups of 7 patients) received either 1g or 2 g paracetamol tablets, 1g or 2g bicarbonate paracetamol tablets or 2g IV propacetamol. After 40 minutes IV propacetamol gave a median plasma concentration of 85 micromol/l (range 65-161). 11 out of 28 (40%) of the patients given paracetamol orally showed undetectable plasma concentrations of paracetamol after 40 minutes. At 80 minutes after oral paracetamol the median (range) plasma concentrations were 36 (0-90) and 129 (21-306) micromol/l for the 1- and 2-g groups respectively. Three of fourteen patients who received 1g had a plasma paracetamol concentration of <10 micromol/l (8). The study did not report clinical outcomes i.e. pain relief, although pain was assessed by VAS and treated when VAS values were>4, but no details are given. A comparison of the analgesic efficacy of single doses of propacetamol 2g IV and paracetamol 1g orally in 323 patients with moderate pain following hallux valgus plasty, showed a significantly greater and longer analgesic effect with the parenteral form (9). Duration of follow-up was 6 hours. IV vs Rectal Absorption of paracetamol following rectal administration is slower and more variable than with IV or oral administration (5,7,10). High initial doses are needed to achieve therapeutic plasma concentrations (7) and therefore the rectal route is not the preferred route of administration of paracetamol for the immediate relief of post-operative pain (5). In the UK the acquisition cost of paracetamol suppositories may be higher than that of the injection, depending on brand and strength (11).! Therapeutic efficacy and tolerability Paracetamol is a well-tolerated analgesic when used at normal dosages for the acute management of mild-to-moderate post-operative pain (5). Where alternative routes are unavailable, IV paracetamol is mostly used in association with NSAIDs and opioids to allow a reduced dose of these analgesics, that have a worse adverse effect profile, to be given (5), rather than as monotherapy (5,10). The Summary of Product Characteristics (SPC) states that frequent adverse reactions at the injection site have been reported during clinical trials (pain and burning sensation) (1). However, the incidence of local adverse events such as injection-site pain and contact dermatitis is significantly lower with IV paracetamol compared with propacetamol (4,10) and comparable to placebo in two studies: 2% (4,12) and 0%(13). A number of systematic reviews have assessed the effectiveness of adding a non-opioid to (PCA) morphine for pain relief and reduction of morphine-related side effects following surgery (14).These are briefly summarised below: Paracetamol plus morphine Remy et al(15) showed that paracetamol (including propacetamol) combined with PCA morphine results in a pooled mean reduction of 9mg in morphine consumption in the first 24 hours after surgery [95% CI: -15 to -3] equivalent to a 20% reduction. Seven s, mainly in orthopaedic and spinal surgery, were included. Five studies used IV paracetamol, one used oral and one used IV plus rectal paracetamol. There were 265 patients in the group with PCA morphine plus paracetamol and 226 patients in the group with PCA morphine alone. There was no statistically significant reduction in morphine-related adverse effects including urinary retention, pruritus and sedation (OR 1.3 for sedation; 95% CI 0.79 TO 2.16; P=0.3). Paracetamol administration resulted in a non-significant reduction in PONV (OR = 0.99; 95% CI, 0.64 to 1.55; P=0.98). Patient satisfaction as assessed by verbal rating scales did not differ between the groups. Elia et al (16) showed that paracetamol (including propacetamol) reduced 24-hour morphine consumption by 8.3mg [95% CI, -10.9 to -5.7]. However, there was no statistically significant reduction in PONV or sedation (16). Fifty -two (4,893 patients undergoing orthopaedic, abdominal, gynaecological, spinal or thoracic surgery) were included. This review also assessed the effect of NSAIDs and COX-2 inhibitors. These were associated with a statistically significant increase in adverse effects: surgical bleeding complications and renal failure, respectively. No adverse effects were noted for paracetamol (16). A more recent systematic review compared the effectiveness of paracetamol, NSAIDs and COX-2 inhibitors in reducing cumulative morphine consumption for the first 24 hours after surgery, and associated adverse effects, when used as part of multimodal analgesia following major surgery (14), including thoracic, orthopaedic, gynaecological, obstetric and general surgery. Sixty studies were identified, 40 of which were from the previous review (16) and 20 new trials. Only 5 studies were identified that directly compared paracetamol and NSAIDs. Seven studies compared paracetamol vs. placebo. Of the 12 paracetamol studies, 9 used IV paracetamol and 3 used oral and/or rectal administration. Data was combined from 56 trials that randomised patients to four treatments including placebo. The main analysis was mixed treatment comparison (MTC) evaluating the relative effects of the four treatment classes: paracetamol, NSAIDs, COX-2 inhibitors and placebo. The mean

difference in 24h morphine consumption for paracetamol was -6.34mg; 95% CI -9.02 to -3.65. NSAIDs and COX-2 inhibitors were more effective than paracetamol, but the differences were small and probably of limited clinical significance. Paracetamol was well-tolerated, with no reports of surgical bleeding, compared to 2.4% of participants receiving a NSAID, based on 6 trials (n = 695) NSAIDs were only slightly more superior to paracetamol in reducing PONV (RR 0.78; 95% CI 0.51 to 1.20) and sedation (RR 0.35; 95% CI 0.04 to 3.00) in patients on PCA morphine. There are other studies of IV paracetamol for post-operative pain which did not meet the inclusion criteria for these systematic reviews (14). Some of these are summarised below.

Table 1. Studies of IV paracetamol for pain relief after cardiac surgery Ref Trial design Trial population Eremenko Randomised 45 patients 2008 17 blind, after CABG placebocontrolled trial Lahtinen Randomised, 2002 18 double blind, placebocontrolled trial 79 patients after CABG Petterson 80 patients 2005 19 after CABG Cattabriga Randomised, 2007 20 double blind, placebocontrolled trial 113 patients after cardiac surgery. All patients received tramadol for 72h. Treatment Primary outcome(s) Results Paracetamol 1g IV (n=22) 30 min before extubation and then every 6h for 18h Propacetamol 2g (n=40) IV 6-hourly for 72h Paracetamol 1g IV(n=39) or PO(n=38)every 6h after extubation for 15h or 14h Paracetamol 1g IV (n=56) or placebo (n=57) 15 min before the end of surgery and every 6h for 72h. Use of rescue analgesic (promedol IM 10mg) Mean cumulative oxycodone consumption via PCA device at the end of 72h Mean cumulative ketobemidone administration during the study period VAS pain scores and PONV Pain as assessed by VAS. Cumulative dose of rescue IV morphine over 72h 36% reduction in mean total use of promedol (p=0.019). Reduction in oxycodone dose of 18.3 mg; 95% CI ( - 6.1 to - 42.7) propacetamol vs placebo, (p=0.15). Mean dose of ketobemidone : IV paracetamol 17.4 ± 7.9mg vs PO paracetamol 22.1 ± 8.6mg (p=0.016).no difference in incidence of PONV & in VAS scores At 12,18 and 24 h, pain scores significantly lower in paracetamol group (p=0.0041, 0.0039, 0.0044 respectively) 48mg vs 97mg (p=0.274) paracetamol vs placebo)

Table 2. Studies of IV paracetamol for pain relief in other types of surgery Ref Trial design Van Aken Double 2004 21 blind Varrassi Double 1999 22 blind Zhou Double 2001 23 blind Trial population Treatment Primary outcome(s) Results 95 patients undergoing thirdmolar surgery 200 women after hysterectomy 164 patients after hip or knee replacement surgery IV propacetamol 2 g (n=31), vs. IM morphine10 mg (n=30) vs. placebo (n= 34). Five hours later, readministered at half of the previous dosages Two IV doses of propacetamol 2 g (n=87) or ketorolac 30mg (n=89) IV propacetamol 2 g (n=57), IV ketorolac 30mg (n=27), 15mg (n=28), placebo (n=52) Pain relief scores at 10 hours and other measures of analgesia Total dose of PCA morphine over 12h Pain intensity over 6h assessed by VAS and VRS and pain relief assessed by a categorical scale No significant differences were found between propacetamol and morphine, both of which were better than placebo. Adverse events were significantly less frequent in the propacetamol than in the morphine group (p<0.027) Propacetamol 10.6 ± 4.8mg vs. ketorolac 10.2 ± 4.4mg (mean ± SD). Incidence of AE was similar. NS prolongation of bleeding time with ketorolac. NS reduction of gastric pain with paracetamol Pain relief scores for propacetamol superior to placebo (p<0.001) and similar to ketorolac 15mg and 30mg (p <0.05) from 0.75 h to 5h. Glossary VAS VRS NSAID PCA CI PONV OR RR CABG NS AE Visual Analogue Scale Verbal Rating Scale Non-steroidal anti-inflammatory drug Patient-controlled analgesia Confidence intervals Post-operative nausea and vomiting Randomised controlled trial Odds Ratio Risk Ratio Coronary artery bypass graft Not Significant Adverse effects

Medicines Q&As Renal colic A in 165 patients admitted with suspected renal colic compared single IV doses of paracetamol 1g, morphine 0.1mg/kg and placebo for pain relief. Patients were excluded if they needed rescue analgesics within the first 30 minutes of the study, so 146 patients were included in the final analysis. The mean reduction in VAS pain intensity scores at 30 minutes was 43 mm for paracetamol (95% CI 35 to 51mm), 40 (29 to 52 mm) for morphine, and 27 (19 to 34 mm) for placebo. There was no difference in pain intensity reduction between paracetamol and morphine. At least one adverse event was experienced by 11(24%) receiving paracetamol 16(33%) receiving morphine and 8(16%) in the placebo group (24).! Adverse effects/precautions/potential risks Cases of accidental overdose have been reported during treatment with IV paracetamol 10mg/mL solution for infusion. In most cases this occurred in infants and neonates (25). However there are reports of clinical incidents involving paracetamol overdose in adult patients weighing less than 50kg, where the dose was not adjusted according to the patient s weight (26,27). Failure to reduce the dose appropriately may result in paracetamol-induced liver toxicity. This could lead to hepatic failure and death (26,27). The British National Formulary (BNF) advises that the maximum daily dose of infusions should be also reduced to 3 g for patients with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition, or dehydration (11). In addition, since the infusion is presented in a rigid container (glass bottle), close monitoring is needed during administration and it must be stopped at the end of the infusion when the bottle is empty, in order to avoid air embolism (1,28). Summary! Intravenous (IV) paracetamol is licensed for the short-term treatment of moderate pain, especially following surgery, and for the short-term treatment of fever, when administration by the IV route is clinically justified by an urgent need to treat pain or hyperthermia and/or when other routes of administration are not possible.! The main advantages of IV paracetamol are: when GI motility is reduced in the immediate post -operative period or when rapid establishment of analgesia is required. Studies have shown a reduction in morphine/opioid requirements; however sedation and post-operative nausea and vomiting are not reduced! IV paracetamol has been shown to achieve therapeutic plasma concentrations well above the therapeutic range within 40 minutes of administration, whereas early plasma concentrations following oral administration of paracetamol may vary, and in some cases may remain subtherapeutic, unless a loading dose has been given. Absorption of paracetamol following rectal administration is slower and more variable than with IV or oral administration therefore this is not a suitable alternative if the oral route is not appropriate! A large proportion of the efficacy data on IV paracetamol is derived from studies of IV propacetamol, a pro-drug of paracetamol. 2g IV propacetamol has been shown to be therapeutically equivalent to 1g IV paracetamol.! There are several studies of the use of IV paracetamol in patients with severe pain post surgery as an opioid-sparing agent and a number of systematic reviews have assessed the effectiveness of adding paracetamol to (PCA) morphine for pain relief and reduction of morphine-related side effects following surgery. IV paracetamol was used in most of the included studies. Paracetamol reduced the mean 24 hour morphine consumption by 6 to 9mg, but overall there was no statistically significant reduction in post-operative nausea and vomiting. Paracetamol was well tolerated, compared to NSAIDs and COX-2 inhibitors.! Caution must be used when IV paracetamol is given to children or adults weighing less than 50kg, as the dose has to be adjusted according to body weight. The dose should also be reduced in patients with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition, or dehydration. Failure to reduce the dose appropriately may result in paracetamol-induced liver toxicity. This could lead to hepatic failure and death.! IV paracetamol has been shown to be effective and well-tolerated in the management of moderate pain immediately after surgery, but care must be taken to dose according to the licensed recommendations (see above).! In order to avoid adverse effects and unnecessary costs it is recommended to switch to oral paracetamol as soon as this administration route is possible. Limitations This Q&A discusses the evidence from studies in adults. The use in infants and children is not discussed. For full prescribing information please refer to the Summary of Product Characteristics Disclaimer Medicines Q&As are intended for healthcare professionals and reflect UK practice. Each Q&A relates only to the clinical scenario described. Q&As are believed to accurately reflect the medical literature at the time of writing. The authors of Medicines Q&As are not responsible for the content of external websites and links are made available solely to indicate their potential usefulness to users of NeLM. You must use your judgement to determine the accuracy and relevance of the information they contain. See NeLM for full disclaimer. Acknowledgements Dr Hannah Blanshard, Consultant Anaesthetist, Bristol Royal Infirmary References (1) Summary of Product Characteristics - Perfalgan (paracetamol). Bristol-Myers Squibb Pharmaceuticals Ltd. Accessed via http://www.medicines.org.uk/emc/medicine/14288/spc/perfalgan+10mg+ml++solution+for+infusion/ on 19/08/10 [date of revision of the text 29 April 2010]. (2) Tzortzopoulou A et al. Single dose propacetamol or IV paracetamol for postoperative pain (Protocol) The Cochrane Collaboration) 2009 (3) Flouvat B et al. Bioequivalence study comparing a new paracetamol solution for injection and propacetamol after single intravenous infusion in healthy subjects. Int J Clin Pharmacol Ther 2004; 42: 50-7 (4) Duggan ST and Scott LJ. Intravenous paracetamol(acetaminophen).drugs 2009;69:101-13 (5) Harding J. Postoperative pain management. Is there a role for intravenous paracetamol in postoperative pain relief? Pharmacy in Practice. March/April 2009 p.67-71 (6) Kennedy JM and van Rij AM. Drug absorption from the small intestine in immediate postoperative patients. Br J Anaesth 2006;97:171-80 (7) Oscier CD and Milner QJW. Peri-operative use of paracetamol. Anaesthesia 2009; 64: 65-72 (8) Pettersson PH et al. Early bioavailability of paracetamol after oral or intravenous administration. Acta Anaesthesiol Scand 2004;48:867-70 (9) Jarde O et al. Parenteral versus oral route increases paracetamol efficacy. Clin Drug Invest 1997; 6: 474-481 (10) Malaise O et al. Intravenous paracetamol: a review of efficacy and safety in therapeutic use. Future Neurology 2007;2:673-88 (11) Joint Formulary Committee. British National Formulary. no 60 ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain. Accessed via http://bnf.org/bnf/ on 24.11.10 (12) Anonymous. Intravenous paracetamol (acetaminophen): a guide to its use in pain and fever. Drugs and therapy perspectives 2009;25:5-8 (13) Moller PL et al. Intravenous acetaminophen (paracetamol): comparable analgesic efficacy, but better local safety than its prodrug, propacetamol, for postoperative pain after third molar surgery. Anesthesia and analgesia 2005;101:90-6 (14) Mc Daid C et al. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review Health Technology Assessment 2010; Vol. 14: No. 17 accessed via http://www.hta.ac.uk/fullmono/mon1417.pdf on 31.8.10

Medicines Q&As (15) Remy C et al. Effects of acetaminophen on morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials. Br J Anaesthesia 2005;94:505-13 (16) Elia N et al. Does multimodal analgesia with acetaminophen, nonsteroidal anti-inflammatory drugs, or selective cyclooxygenase -2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology 2005;103:1296-304 (17) Eremenko AA, Kuslieva EV. Analgesic and opioid-sparing effects of intravenous paracetamol in the early period after aortocoronary bypass surgery. Anesteziologiia i reanimatologiia 2008; 5:4-11 (18) Lahtinen P et al. Propacetamol as adjunctive treatment for postoperative pain after cardiac surgery. Anesth Analg 2002;95:813-19 (19) Pettersson PH et al. Intravenous acetaminophen reduced the use of opioids compared with oral administration after coronary artery bypass grafting. J Cardiothorac Vasc Anesth 2005;19:306-9 (20) Cattabriga I et al. Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized trial. Eur J Cardiothorac Surg 2007;32:527-31 (21) Van Aken H et al. Assessing analgesia in single and repeated administrations of propacetamol for postoperative pain: comparison with morphine after dental surgery. Anesth Analg 2004;98:159-65 (22) Varrassi G et al. A double-blinded evaluation of propacetamol versus ketorolac in combination with patient-controlled analgesia morphine: analgesic efficacy and tolerability after gynecologic surgery Anesth Analg 1999;88:611 16 (23) Zhou TJ at al. Propacetamol versus ketorolac for treatment of acute postoperative pain after total hip or knee replacement. Anesth Analg 2001; 92:1569-75 (24) Bektas F et al. Intravenous paracetamol or morphine for the treatment of renal colic: a randomized, placebo-controlled trial. Ann Emerg Med 2009; 54: 568-74 (25) MHRA Drug Safety Update July 2010;3 (12): 2-4 accessed via http://www.mhra.gov.uk/publications/safetyguidance/drugsafetyupdate/con087803 on 14.9.10 (26) Claridge LC et al. Lesson of the Week. Acute liver failure after administration of paracetamol at the maximum recommended daily dose in adults. BMJ 341:doi:10.1136/bmj.c6764 (Published 2 December 2010) Accessed via www.bmj.com on 7.12.10 (27) NHS Greater Glasgow and Clyde. Postscript Acute. Issue 1, July 2010 IV Paracetamol Risk of Hepatic Damage. Accessed via http://www.glasgowformulary.scot.nhs.uk/ps%20acute/ps%20acute%20issue%201.pdf on 21.10.10 (28) Pierson R, Coupe M. Reducing the risk of air embolism following administration of IV paracetamol. Anaesthesia 2008; 63:96-107 Embase: (PARACETAMOL/iv,pa [Limit to: Human] and exp *PAIN/ [Limit to: (Clinical Trials Clinical Trial) and Human]) PARACETAMOL/po and PARACETAMOL/iv,pa and exp *PAIN/ [Limit to: (Clinical Trials Clinical Trial) and Human]) Micromedex: Acetaminophen Drug Evaluation Monograph In-house database/resources Google : intravenous paracetamol site:nhs.uk NELM: Paracetamol infusions OR Intravenous paracetamol Dr Hannah Blanshard, Consultant Anaesthetist, Bristol Royal Infirmary Quality Assurance Prepared by Julia Kuczynska, South West Medicines Information and Training, University Hospitals Bristol NHS Foundation Trust Date Prepared August 2010 Checked by Trevor Beswick, South West Medicines Information and Training, University Hospitals Bristol NHS Foundation Trust Date of check 30 th December 2010 Search strategy Medline: exp *ACETAMINOPHEN and [ exp *INFUSIONS, INTRAVENOUS or exp *INJECTIONS, INTRAVENOUS] or "paracetamol infusion".ti,ab or "paracetamol injection*".ti,ab] [Limit to: Humans]