European Review for Medical and Pharmacological Sciences 2008; 12(Suppl 1): 119-127 New approaches to the treatment of opioid-induced constipation P. HOLZER Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz (Austria) Abstract. – Opiates are indispensable Introduction for the treatment of moderate to severe pain. The gastrointestinal tract is one of the major Opium derived from the unripe seed capsules victims of the undesired effects of opiates, be- cause the enteric nervous system expresses of Papaver somniferum has been used since an- all major subtypes of opioid receptors. As a cient times to treat diarrhoea. We now know that result, propulsive motility and secretory the biological effects of opium are due not only processes in the gut are inhibited by opioid to morphine and codeine but also other drugs analgesics, and the ensuing constipation is such as papaverine, all of which affect the func- one of the most frequent and troublesome ad- tion of the gastrointestinal (GI) tract. Despite verse reactions. Many treatments involving laxatives, prokinetic drugs and opioid-sparing many attempts to develop other strong pain ther- regimens have been explored to circumvent apeutics, opioid analgesics have remained the opioid-induced bowel dysfunction, but the mainstay of therapy in many patients with mod- outcome has in general been unsatisfactory. erate to severe pain. However, the use of opioid Specific antagonism of peripheral opioid re- analgesics is associated with a number of adverse ceptors offers a more rational approach to the effects among which those on the GI tract are management of the adverse actions of opioid most troublesome in terms of frequency and analgesics in the gut. This goal is currently addressed by the use of opioid receptor an- severity. The constipation associated with opioid tagonists with limited absorption such as oral medication can be disabling to a degree that opi- naloxone and by the development of peripher- oid treatment needs to be reduced or even aban- ally restricted opioid receptor antagonists doned. The traditional approach to ameliorate such as methylnaltrexone and alvimopan. opioid-induced constipation is laxative co-med- These investigational drugs hold considerable ication which, however, can be both ineffective promise in preventing constipation due to opi- 1-3 ate treatment, whereas the analgesic action of and distasteful to the patient . opiates remains unabated. Postoperative ileus The spectrum of adverse opioid actions on the associated with opioid-induced postsurgical gut reflects the ability of these analgesic drugs to pain control is likewise ameliorated by the directly interact with pathways of the enteric ner- compounds. With this proof of concept, sever- vous system that regulate GI motility and secre- al phase III studies are under way to define op- tion4-8. In addition, there is evidence that some GI timal dosage, dosing regimen as well as long- effects of opioid receptor agonists can be mediat- term efficacy and safety of methylnaltrexone 9 and alvimopan. In addition, there is prelimi- ed by opioid receptors in the brain . However, ex- nary evidence that these peripherally restrict- perimental and clinical studies with opioid recep- ed opioid receptor antagonists may act as tor antagonists that are unable to enter the brain prokinetic drugs in their own right. have shown that the adverse GI effect profile of opioid receptor agonists is essentially peripheral Key Words: in origin9. Consequently, peripherally restricted Alvimopan, Methylnaltrexone, Naloxone, Opioid opioid receptor antagonists (PRORAs) such as peptides, Enteric nervous system, Opioid-induced N-methylnaltrexone and alvimopan represent a bowel dysfunction, Constipation, Peripherally re- significant advance in improving opiate therapy stricted opioid receptor antagonists, Prokinetic ef- of pain2,7. The current review starts by providing fects. a brief overview of the neurobiological mecha- Corresponding Author: Peter Holzer, PhD; e-mail: [email protected] 119 P. Holzer nisms whereby opioids cause constipation. After The presence of an elaborate opioid system (Fig- describing the clinical features of opioid-induced ure 1) in the gut explains why exogenous opioid bowel dysfunction (OBD) the article goes on to analgesics inhibit GI function. Met-enkephalin, discuss the emerging strategies to avoid OBD leu-enkephalin, β-endorphin and dynorphin are and the expanding range of indications in which among the endogenous opioid peptides occurring PRORAs are likely to be of therapeutic benefit. in the GI tract where they have been localized to both neurons and endocrine cells of the mu- cosa2,4,5,8,13. Further analysis has revealed that The Opioid System in opioid peptides are present in distinct classes of the Gastrointestinal Tract enteric neurons, notably in myenteric neurons projecting to the circular muscle and in neurons Independently of their plant, mammalian or of descending enteric pathways11-13. Opioid re- synthetic origin, opioids are neuroactive sub- ceptors of the µ-, κ- and δ-subtype have been lo- stances, the actions of which are mediated by the calized to the GI tract of rodents and humans, but principal µ-, κ- and δ-opioid receptors. Many their relative distribution varies with GI layer, GI neuroactive drugs act on the gut because the ali- region and species2,8,13. In the human gut, µ-opi- mentary canal is equipped with the largest collec- oid receptors are present on myenteric and sub- tion of neurons outside the brain, known as the mucosal neurons and on immune cells in the enteric nervous system (ENS). The enteric neu- lamina propria13. rons originate from the myenteric and submucos- al plexuses, supply all layers of the alimentary canal and thus are in a position to regulate virtu- Opioid Physiology and Pharmacology in ally each aspect of digestion10-12. Many of the the Gastrointestinal Tract transmitters and neuropeptides occurring in the brain are also expressed by the ENS, and the When released from enteric neurons, opioid same is true for transmitter and neuropeptide re- peptides modify GI function by interaction with ceptors. Thus, enteric neurons synthesize and re- opioid receptors present on the enteric circuitry lease not only acetylcholine, substance P, nitric controlling motility and secretion. The inhibitory oxide, adenosine triphosphate, vasoactive intesti- effect of opioid receptor agonists on peristalsis in nal polypeptide and 5-hydroxytryptamine but al- the guinea-pig small intestine is thought to arise so opioid peptides as their transmitters. primarily from interruption of transmission with- Figure 1. Schematic overview of the gastrointestinal opioid system rele- vant to constipation. 120 New approaches to the treatment of opioid-induced constipation in enteric nerve pathways governing muscle ac- duced inhibition of muscle activity2,8. Propulsive tivity7,8,14. Transmission is blocked both via motility in the rat intestine is blocked by δ- and µ-, presynaptic and postsynaptic sites of action on but not κ-, opioid receptor agonists5, whereas enteric neurons, whereby the release and action peristalsis in the guinea-pig intestine is sup- of transmitters are attenuated5,14. It is important pressed by activation of κ- and µ-, but not δ-, opi- to realize that opioid receptor agonists can inter- oid receptors18, much as opiate-induced inhibition rupt both excitatory and inhibitory neural inputs of cholinergic transmission in the guinea-pig gut to GI muscle14. Suppression of excitatory neural is mediated by µ- and κ-opioid receptors. inputs causes inhibition of the release of excitato- Although the available evidence indicates that ry transmitters such as acetylcholine and block- OBD is mediated by opioid receptors in the ade of distension-induced peristaltic contrac- gut2,8, there are experimental data to show that tions, whereas blockade of inhibitory neural in- opioids acting within the brain can also influence puts results in depression of nitric oxide release GI function. Thus, intradural injection of opioid from inhibitory motor neurons, disinhibition of analgesics delays intestinal transit at doses that GI muscle activity, elevation of resting muscle are considerably lower than equieffective intra- tone and non-propulsive motility patterns5,7,8,14,15. venous doses9. However, opiate-induced block- Depending on whether interruption of excita- ade of gut motility correlates better with opiate tory or inhibitory neural pathways is prevailing, concentrations in the gut than with opiate con- muscle relaxation or spasm will ensue in re- centrations in the brain19. In addition, the N- sponse to opiate administration. In addition, opi- methyl quaternary analogues of naloxone and oids may directly activate the interstitial naltrexone, which do not cross the blood-brain cell–muscle network. As a result, µ-opioid recep- barrier, are able to fully antagonize the effects of tor agonists inhibit gastric emptying, increase py- morphine in the canine and rat intestine2,9. It fol- loric muscle tone, induce pyloric and duodenoje- lows that the adverse influence of opiates on GI junal phasic pressure activity, disturb the migrat- function results primarily from interaction with ing myoelectrical complex, delay transit through opioid receptors in the gut, an inference that is the small and large intestine, and elevate the rest- backed by the experimental and clinical effects ing anal sphincter pressure2,8,14.