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Table of Contents
EDITORIAL
Year : 2012  |  Volume : 28  |  Issue : 4  |  Page : 426-427

Pain or constipation: A difficult choice


Department of Anaesthesiology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication4-Oct-2012

Correspondence Address:
Trikha Anjan
Department of Anaesthesiology, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9185.101884

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How to cite this article:
Anjan T, Singh P M. Pain or constipation: A difficult choice. J Anaesthesiol Clin Pharmacol 2012;28:426-7

How to cite this URL:
Anjan T, Singh P M. Pain or constipation: A difficult choice. J Anaesthesiol Clin Pharmacol [serial online] 2012 [cited 2019 Aug 22];28:426-7. Available from: http://www.joacp.org/text.asp?2012/28/4/426/101884

One of the less reported side effects in the immediate postoperative period in nongastrointestinal surgery is constipation. This usually is because of use of opioids during the perioperative period. Opioids inhibit peristalsis by interrupting the transmission within the enteric nerve pathways that govern gut muscle contractions. [1] This action of opioids is mediated through δ-, κ-, and μ-opioid receptors. [2],[3]

This inhibition leading to constipation is locally mediated unlike the analgesic action of the opioids that is due to their central action. It is but natural that administration of pharmacological agents that can prevent/inhibit this local action of opioids in the gut without affecting their central analgesic action could be useful in preventing inhibition of gut motility and thus constipation. One such logical combination that has recently being made available in Europe is a fixed drug formulation of oxycodone and naloxone (Targin™). [4]

Naloxone is a logical choice to antagonize the locally mediated inhibition of peristalsis by opioids, as its oral bioavailability is only 2% because of very high first pass metabolism. [5] There have been recent reports of success of such combinations in terms of prevention of constipation without loss of analgesia for chronic pain-both cancer and non-cancer. [6],[7],[8],[9]

The use of such a fixed dose combination in acute pain settings is still limited. Most of the postsurgical patients except those involving the gastrointestinal (GIT) surgeries are allowed oral intake after 4-6 h or after 24 h. Oral opioids, which are high ceiling analgesics, are not popular in these settings because of associated constipating effect. Interestingly, opioids continue to be used intravenously in the same settings even though they are associated with constipation. Use of intravenous opioids and oral antagonist does not seem to be a logical choice because of compliance issues and possibly difficulty in titration of the intravenous and the oral medications. An oral fixed dose combination would be able to eliminate both these problems [7] and would give anesthesiologists more options of using longer acting, high ceiling analgesics in the perioperative period.

Postoperative nausea vomiting is another major concern against use of opioids especially in the postoperative period, when actually an analgesic is needed the most. Naloxone is known to alleviate opioid-induced nausea vomiting [10] and has been classically used in combination with opioids for the same. The antiemetic action is known to be caused by its direct action on peripheral gut receptors with contribution from central central nervous system (CNS) receptors as well. Thus, such an oral combination would also prove beneficial to prevent postoperative nausea vomiting and would improve patient satisfaction toward surgery.

The advantages of using agonist/antagonist hold promise for the analgesic therapy of cancer pain management where home-based oral therapy forms the mainstay of the analgesia. With chronic opioid therapy, most of the side effects decrease over time, except for constipation that rather worsens with time and is thus a major cause of discontinuation. [11] This constipation is resistant to even aggressive laxative therapies and adds further to its adverse effects. [12]

Two other antagonists that have been introduced for managing opioid-induced constipation are N-methyl-naltrexone (Relistor™) and alvimopan (Entereg™). The absorption of N-methyl naltrexone after oral administration is very low (oral bioavailability <1%) and due to its very low lipophilicity, it does not cross the blood-brain barrier and thus can antagonize the analgesia. [13] The major disadvantages noted with both oral naloxone and N-methyl naltrexone are that they are associated with unpleasant gut cramps and diarrhea. [8],[13] The research has shown that for prevention of constipation alone, a selective μ-receptor antagonist would be the most appropriate therapy. [14]

Alvimopan is a selective μ-receptor antagonist and has not only shown decreased incidence of associated diarrhea, but also does not prolong the GIT transit times of drugs and thus does not interfere with their absorption rates. This is an added advantage over its congeners as cancer patients are on multiple oral drugs and hence the rate of drug absorption and gut mobility are important considerations. [15] Both N-methyl naltrexone and alvimopan do not precipitate withdrawal symptoms in patients on prolonged opioid intake, unlike oral nalaxone, due to their extremely poor CNS penetration. [15],[16]

In the near future, we are likely to see combinations of these drugs with longer acting oral opioids for both acute and chronic pain. In totality, one must not forget that early mobilization after surgery itself enhances the bowel mobility. Thus, both the above goals can be only achieved with optimal pain control. One must look toward multimodal modes of analgesia possibly including opioid antagonists to achieve best pain relief with minimal side effects.

 
  References Top

1.Tonini M, Waterman SA, Candura SM, Coccini SM, Costa M. Sites of action of morphine on the ascending excitatory reflex in the guinea-pig small intestine. Neurosci Lett 1992;144:195-8.  Back to cited text no. 1
    
2.Bauer AJ, Sarr MG, Szurszewski JH. Opioids inhibit neuromuscular transmission in circular muscle of human and baboon jejunum. Gastroenterology 1991;101:970-6.  Back to cited text no. 2
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3.Chamouard P, Klein A, Martin E, Adloff M, Angel F. Regulatory role of enteric kappa opioid receptors in human colonic motility. Life Sci 1993;53:1149-56.  Back to cited text no. 3
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4.Targin. New treatment for chronic pain sufferers now launching across Europe. Pharmalive [online]. January 26, 2009. Available from: http://www.pharmalive.com/News/index.cfm?articleid=599896. [Last accessed on 2012 Jul 13].  Back to cited text no. 4
    
5.Holzer P. Opioids and opioid receptors in the enteric nervous system: from a problem in opioid analgesia to a possible new prokinetic therapy in humans. Neuroscience Lett 2004;361:192-5.  Back to cited text no. 5
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6.Meissner W, Leyendecker P, Mueller-Lissner S, Nadstawek J, Hopp M, Ruckes C, et al. A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain 2009;13:56-64.  Back to cited text no. 6
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7.Simpson K, Leyendecker P, Hopp M, Müller-Lissner S, Löwenstein O, De Andrés J, et al. Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain. Curr Med Res Opin 2008;24:3503-12.  Back to cited text no. 7
    
8.Vondrackova D, Leyendecker P, Meissner W, Hopp M, Szombati I, Hermanns K, et al. Analgesic efficacy and safety of oxycodone in combination with naloxone as prolonged release tablets in patients with moderate to severe chronic pain. J Pain 2008;9:1144-54.  Back to cited text no. 8
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9.Sykes NP. An investigation of the ability of oral naloxone to correct opioid-related constipation in patients with advanced cancer. Palliat Med 1996;10:135-44.  Back to cited text no. 9
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10.Yeh YC, Lin TF, Wang CH, Wang YP, Lin CJ, Sun WZ. Effect of combining ultra low-dose naloxone with morphine in intravenous patient-controlled analgesia: the cut-off ratio of naloxone to morphine for antiemesis after gynecologic surgery. J Formos Med Assoc 2008;107:478-84.  Back to cited text no. 10
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11.Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs 2003;63:649- 71.  Back to cited text no. 11
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12.Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg 2001;182:11-8.  Back to cited text no. 12
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13.Foss JF. A review of the potential role of methylnaltrexone in opioid bowel dysfunction. Am J Surg 2001;182 (5A Suppl):19S-26S.  Back to cited text no. 13
    
14.Liu SS, Hodgson PS, Carpenter RL, Fricke JR Jr. ADL 8-2698, a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, prevents gastro-intestinal effects of intravenous morphine without affecting analgesia. Clin Pharmacol Ther 2001;69:66-71.  Back to cited text no. 14
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15.Schmidt WK. Alvimopan (ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg 2001;182 (5A Suppl):27S-38S.  Back to cited text no. 15
    
16.Goodheart CR, Leavitt SB. Managing Opioid Induced Constipation in ambulatory patients. Pain Treatment Topics 2006. Available from: http://www.pain-topics.org/pdf/Managing_Opioid-Induced_Constipation.pdf. [Last accessed on 2012 Jul 13].  Back to cited text no. 16
    




 

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