Peripheral opioid receptor agonists for analgesia: A comprehensive review

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1 REVIEW ARTICLE Peripheral opioid receptor agonists for analgesia: A comprehensive review Nalini Vadivelu, MD; Sukanya Mitra, MD; Roberta L. Hines, MD ARTICLE INFO Keywords: peripheral opioid receptors peripheral opioid agonists peripheral mu-/kappa-/delta-opioid receptor agonists inflammatory pain neuropathic pain Article history: Received 3 June 2010 Received in revised form 26 September 2010 Accepted 27 October 2010 DOI: /jom Journal of Opioid Management, All Rights Reserved. ABSTRACT Background: It is established that opioid receptors are present in the dorsal root ganglia and the central as well as peripheral terminals of primary afferent neurons. Now, it has been shown that peripheral terminals of afferent nerves can be the sites of the intrinsic modulation of nociception and that opioid analgesia can be mediated by peripheral opioid receptors as well. Aim: This review focuses on two areas: the first on describing the peripheral opioidergic system, and the second on the review of the current state of development of peripherally active opioid receptor agonists with their potential clinical applications. Methods: Online and manual search using key words such as peripheral opioid receptors, peripheral (or peripherally restricted) opioid agonists, and peripheral mu-, kappa-, and delta-opioid receptor agonists, followed by full-text access and further cross-referencing. Results: The obvious theoretical advantage of using these molecules is that analgesia is achieved while avoiding the bothersome-to-dangerous centrally mediated adverse effects of centrally acting opioids. Molecules known for their central action (eg, morphine) have been used in peripheral tissues (joints, bone, teeth) with reasonable but varied success. Over the last years, several molecules with peripherally restricted opioid agonist activity have been developed and several more are in the clinical pipeline. Although none is available as an approved medication till date, a few (eg, the peripherally restricted kappa-agonist FE200665, also known as CR665) have completed phase I clinical trials and currently in phase II. Others such as loperamide, which is approved for use as an antidiarrheal drug, have been found to be variably useful as a peripherally acting opioid analgesic. Conclusions: Substantive research is currently underway and this is an exciting research area for both basic and applied clinical fields. Various ways to enhance peripheral opioid analgesia are suggested. INTRODUCTION Opioid receptors (mu, delta, and kappa) are present in the central nervous system and the peripheral nervous system. 1 Earlier it was thought that opioids produced pain control by acting solely within the central nervous system. 2 It is now known that opioid-binding receptors are present in the dorsal root ganglia, the central terminals of primary afferent neurons, and their peripheral terminals as well. 3,4 Opioid receptors in the periphery can be a site for mediating analgesia. 5-7 The use of opioids is associated with unfortunate adverse effects, which can at best be bothersome (eg, nausea and vomiting) or at worst life threatening (eg, respiratory depression). 8 These adverse effects are because of the action of opioids on opioid receptors in the brain. Another major problem associated with continued use of opioids is the development of tolerance and addiction, again because of their central actions. In this regard, peripheral opioid receptor agonists could have important advantages such as decreasing these adverse effects and reducing 55

2 tolerance and addiction liability while maintaining analgesic efficacy. This is the essential rationale behind the growing interest in developing opioid molecules with peripherally restricted site of action. Several animal studies have shown that opioid receptors have anti-inflammatory as well as antinociceptive actions in inflamed tissues. 9,10 It appears that the number of peripheral opioid receptors increases in the presence of inflammation. 5 Immune cells present in inflamed tissues can release endogenous opioids that are peripheral opioid receptor agonists. Peripheral opioid agonists can be endogenous or exogenous. Injection of exogenous opioids locally to peripheral inflamed tissues caused potent local naloxone-reversible pain relief As a clinical corollary, there is an interest in the use of peripheral injections of opioids for postoperative pain relief as seen with the use of intra-articular (IA) injection of opioids after knee joint surgery. 9 Many molecules that are peripherally restricted opioid agonists are in various stages of development. This is an exciting area of current ongoing research. The literature on this topic was gleaned through multiple PubMed (time frame of search 1966 to April 2010) and Google Scholar online searches, using key terms such as peripheral opioid receptors, peripheral (or peripherally restricted) opioid agonists, and peripheral mu-, kappa-, and delta-opioid receptor (MOR, KOR, and DOR, respectively) agonists. Further, online crosslinked references were searched. Following this, we obtained full-text access to as many articles as possible, either by online or by manual library search. From these full-text articles, further relevant cross references were then accessed. This review is organized in two parts, with partial overlap. The first part focuses on the peripheral opioidergic system (peripheral opioid agonists that act on receptors present on the terminals of peripheral sensory nerve terminals), 5,9,13 and the second part focuses on the review of the current state of development of those agents and the associated potential applications in the clinical setting. THE PERIPHERAL OPIOIDERGIC SYSTEM Peripheral opioid receptors Stein et al. 10,13 demonstrated that peripheral opioid receptors are present on the peripheral sensory nerve fibers and their terminals. It is well known that opioid receptors are present in the dorsal root ganglia and in the central terminals of primary afferent neurons. 3 It has also been shown that the characteristics of peripheral opioid receptors are very similar to those in the brain. 4,5 The anti-inflammatory effects of opioids in the periphery is due to the inhibition of calcium-dependent release of excitatory substances such as substance P from the peripheral sensory nerve endings, 14 just as opioids inhibit substance P release from the mammalian spinal cord. 15 This occurs because opioids reduce calcium-dependent action potential duration by increasing potassium conductance, which decrease neuronal firing and transmitter release in the cell bodies of sensory neurons. 16,17 Types of peripheral opioid receptors All three opioid receptors, MOR, KOR, and DOR, are present in the periphery and can be functionally active. 5 The actions of opioids working in the periphery have been studied by using opioid agonists that do not cross the blood-brain barrier and by the application of the opioid dose solely to the periphery. 5 Mu-opioid receptors. MOR ligands are the most potent of the peripheral receptor agonists and bind to mu-opioid peripheral receptors. There is evidence for a functional interaction between MOR and transient receptor potential vanilloid receptor type 1 (TRPV1), which is a capsaicin-sensitive calcium channel-related receptor. TRPV1 and other vanilloid receptors are necessary for the development of inflammatory hyperalgesia. G-protein-coupled prostaglandin receptors have been shown to interact with the TRPV1 receptor through a cyclic adenosine monophosphate (camp)-dependent protein kinase A (PKA) pathway to potentiate TRPV1- mediated capsaicin responses and associated substance P release in the periphery. Vetter et al. 18 have shown that morphine, acting at the peripheral MOR, inhibits adenylate cyclase through the PKA pathway, thereby preventing the potentiation of vanilloid receptors, with a resultant antinociception in inflammation. Morphine 6 glucuronide has been reported to have peripheral antinociceptive effects on inflammatory pain while inducing less nausea and vomiting in humans. 2 Loperamide, which is used as an antidiarrheal drug, has been reported to have peripherally active antinociceptive MOR agonist effect when applied locally to the injured paw of the rat

3 Kappa-opioid receptors. KOR agonists differ from MOR agonists in that they do not cause respiratory depression or constipation and have demonstrated a decreased potential for abuse. 20 The sedative and dysphoric effects of KOR agonists can be avoided by using small systemically inactive doses of kappa-agonists directly to the peripheral injured tissues. There they can activate the peripheral opioid receptor. 6,21 The activation of peripheral opioid receptors is more pronounced in the presence of inflammation if they are used in small systemically inactive doses. They also have a reduced capability to produce tolerance. 22 KOR agonists can produce antinociception especially in neuropathic and inflammatory models without untoward central nervous system side effects. 23 This makes them potentially useful agents for the treatment of pain in the presence of tolerance and physical dependence. It must be remembered, however, that KOR agonists have been shown to cause mechanical allodynia and hyperalgesia in a rat model. Allodynia was induced by a single intrathecal injection of dynorphin, a KOR agonist. This allodynia was blocked by pretreatment with N-methyl-Daspartate (NMDA) receptor antagonists but not by naloxone, thereby indicating the role of NMDA receptors rather than opioid receptors in the genesis of dynorphin-induced allodynia. 24,25 A KOR agonist that has a restricted ability to cross the blood-brain barrier is asimadoline. Machelska et al. 26 studied the effects of this drug on 35 patients undergoing diagnostic arthroscopic knee surgery. Asimadoline given orally at a dose of 10 mg did not adequately produce pain relief. The findings suggested a tendency toward adverse nonopioid receptor-mediated hyperalgesic effects. However, in a rat model, asimadoline produced differentially mediated peripheral actions of antinociception and non-nmda receptor mediated proinflammatory and hyperalgesic effects. 26 Peripheral opioid agonists and immune cells It has been demonstrated that the actions of peripherally acting opioids are closely linked to the immune system. 6 Opioid-binding sites have been shown to be present on immune cells. 27 It is possible that pain can be inhibited by the interaction of the immune system with the peripheral sensory nerve endings. However, the clinical importance of this fact has yet to be confirmed. It has been suggested that opioids modulate the proliferation of immune cells and their functions of chemotaxis, production of superoxides, and mast cell degranulation. 27 Immune cells in inflamed tissues express endogenous opioids. Other factors seen in the presence of inflammation such as endogenous substances (like corticotrophin-releasing hormone [CRH] and cytokines) as well as environmental stimuli can also stimulate the release of peripheral endogenous opioids. These secreted opioids can bind with peripheral opioid receptors on sensory nerves leading to analgesia. When the immune system is suppressed, the secretion of endogenous peripheral opioids is suppressed as well. 13 Peripheral opioid agonists in inflammation Peripheral opioid receptors are present in sensory nerves in both normal tissue and in tissue with inflammation. However, peripheral opioid agonists produce analgesia significantly in the presence of inflammation and insignificantly in normal conditions, suggesting that analgesia is induced by inflammation. The peripheral opioid effects are not easily detectable in normal tissue. However, in the presence of an inflammatory reaction, these effects are detected within minutes to hours leading to the notion that peripheral opioid receptors are pre-existent in peripheral sensory nerve terminals but are able to react with the opioid agonists only in the presence of inflammation. 5,6 There appears to be several hypotheses as to why peripheral opioid receptors are more effective in the presence of inflammation than in the absence of inflammation. Antonijevic et al. 6 showed that the perineurium is a critical determinant for peripheral opioid analgesia. Endogenous opioid peptides have an unrestricted transperineural passage in inflammation allowing contact with sensory nerves, which results in antinociception. The antinociception of fentanyl in noninflamed tissue was also potentiated by inflammation. Another potential reason for these effects seen in inflammation is the increased number of peripheral sensory nerve terminals in inflammation known as sprouting. Yet another reason is the possibility of increased activity and upregulation of opioid receptors in the periphery in the presence of inflammation. Peripherally directed axonal transport of opioid receptors or upregulation is also seen in inflammation. Hassan et al. 5 have showed that axonal transport of opioid receptors in sciatic nerves is increased in peripheral inflammation with resultant increase in the number of opioid receptors on cutaneous nerve fibers. 57

4 The increased neuronal concentration of camp in the presence of inflammation allows the opioids to decrease the excitability of primary afferent neurons. It has been seen that G-protein-binding proteins in neuronal membranes bind more avidly to the opioid receptors in the presence of a low ph that commonly occurs in the presence of inflammation. 28 Less tolerance Stein 9 showed that the IA injection of morphine produces clinical analgesia after knee joint surgery. Stein et al. 22 also showed that in the presence of an abundance of opioid-containing cells in pronounced synovitis, morphine was at least as effective as seen in patients without similar cellular infiltrations. In addition, there was no major downregulation of opioid receptors. They concluded that tolerance occurred less with peripherally than with centrally acting opioids and that opioids expressed in inflamed tissue did not produce tolerance to peripheral morphine analgesia. Therefore, peripherally acting opioids could then be extremely useful for the treatment of chronic inflammatory pain such as arthritis and for patients with tolerance and history of addiction to opioids. Side effects Most opioid agonists relieve pain but are associated with a variety of side effects. These include (a) visceral effects, eg, inhibition of gastrointestinal motor effects 29 such as transit delay and constipation, 30 and (b) centrally mediated side effects including tolerance and physical dependence. 31 Peripheral opioid receptor agonists, by definition, should have the theoretical advantage of being devoid of the centrally mediated adverse effects of opioids. As regards to visceral effects, the three major opioid receptors, MOR, DOR, and KOR, are known to modulate visceral nociception Of these, it has been seen that peripheral KOR agonists can reduce visceral sensation in human studies without constipation and central side effects These are some of the advantages that make the study of peripheral opioid receptor agonists clinically attractive. Visceral pain and peripheral opioid system Opioid receptors associated with sensory innervation of the gastrointestinal tract are derived from cell bodies of the spinal dorsal root ganglia and transported to the afferent terminals of primary afferent neurons. 38 It has been shown that KOR agonists, but not MOR or DOR agonists, significantly attenuate visceral afferent output. 39,40 Colonic distension elicits responses in mechanosensitive pelvic afferent fibers while gastric distension elicits responses in vagal afferent fibers. KOR agonists, eg, fedotozine, reverse the digestive ileus caused by acetic acid-induced visceral pain in rats. 41 Peritoneal irritation induced ileus by chemical means and surgically induced ileus activates an extrinsic inhibitory nervous control of gastrointestinal motility. These pathways involve capsaicin, a selective neurotoxin for fine unmyelinated sensory afferents of primary vagal and spinal afferent neurons. Capsaicin-sensitive neurons are involved in the afferent limb 42 and inhibitory adrenergic neurons in the efferent limb. 43 Capsaicin pretreatment reduces the magnitude of both chemically and surgically induced ileus in rats. 44 Vagal fibers are not involved in peritonealinduced ileus, and sensory afferents traveling with splanchnic nerves are most likely involved. Spinal afferent fibers running with sympathetic nerves have been known to mediate pain. 45 It is seen that corticotrophin-releasing factor (CRF) pathways are also involved in the efferent limb of this pathway. Injection of CRF intracisternally mimics peritoneal irritation-induced ileus. Injection of the CRF antagonist alpha-helical CRF reverses both peritoneal irritation-induced ileus and surgically induced ileus. Satiation and peripheral opioid agonists In a study on human volunteers, Delgado-Aros et al. 46 determined the effects of asimadoline, a KOR agonist, on satiation and gastrointestinal motor and sensory functions in humans. Ninety-one healthy volunteers were randomized in a double-blinded fashion to 0.15, 0.5, or 1.5 mg for asimadoline or placebo orally twice a day for 9 days. Asimadoline delayed the onset of satiation at constant rates of ingestion, allowing greater ingestion of a nutrient liquid meal than placebo without affecting postprandial symptoms. It was seen that asimadoline decreased colonic tone during fasting without affecting postprandial contraction, compliance, or transit. Asimadoline increased pain scores at distensions of 8 and 16 mm Hg but not at higher levels of distension. It appeared to be a safe medication capable of 58

5 increasing acute nutrient intake and decreasing visceral perception in humans in low doses (0.5 mg). It has also been seen that the activity of kappa-opioid agonists are enhanced in the presence of chronic and not acute inflammation of the viscera. Actions of peripheral opioid agonists are reversible The actions of peripheral opioid receptors that can modulate both afferent and efferent function 47 and act on mu-, delta-, and kappa-receptors are reversible by antagonists without central side effects. 10,11 Peripheral antinociception has been demonstrated to a variety of noxious stimuli such as heat, chemicals, and pressure where opioids are applied locally. These peripheral analgesic effects appear to be enhanced in the presence of hyperalgesia or inflammation. 34,48 Capsaicin leads to excitation of neurons that is initially associated with the release of substance P and calcitonin gene-related peptide, leading to an increase in pain perception. 49,50 Intradermal injection of capsaicin in human skin produces burning pain and allodynic/hyperalgesic response. 51 Opioid agonists can act on peripheral opioid receptors and attenuate nociceptive responses that are induced by capsaicin. 52 Ko et al. 53 demonstrated that when small doses of systemically inactive doses of mu- or kappa-agonists were coadministered with capsaicin in the tail of rhesus monkeys, they produced local attenuation of nociceptive responses without central side effects. In another study in rats, these investigators showed that local administration of mu-agonist fentanyl or kappa-opioid agonist U50488-attenuated capsaicin induced thermal hyperalgesia in a dose-dependent manner, suggesting that peripheral MOR and KOR may act on primary afferents to inhibit nociceptive transmission by C fibers. 53 Figure 1 shows the opioid receptor production, transport, and signaling in primary afferent neurons. Figure 2 shows migration of opioid-producing immune cells and opioid secretion in inflamed tissue. POTENTIAL FOR CLINICAL APPLICATIONS Opioid drugs that do not cross the blood-brain barrier can lead to a reduction in or absence of the usual problems associated with opioids, such as the central nervous system side effects of respiratory depression, sedation, tolerance, and addiction and physical dependence. As reviewed earlier, the peripheral opioidergic system has emerged as a Figure 1. Opioid receptor production, transport, and signaling in primary afferent neurons. Opioid receptors (OR) are synthesized in the dorsal root ganglion and transported along intra-axonal microtubules to both the peripheral and central terminals of the primary afferent neuron. Exogenous (EO) or endogenous (OP) opioids activate these receptors, which then couple with inhibitory G proteins (G i/o ). This leads to direct or indirect (through decrease of cyclic adenosine monophosphate [camp]) suppression ( ) of Ca ++ or Na + currents, thus hyperpolarizing the neuronal membrane and finally reducing its excitability. It also leads to attenuation of substance P (sp) release. The net effect is peripherally mediated analgesia. Reprinted with permission from Macmillan Publishers Ltd. 34 major player in the series of events leading to both inflammatory and neuropathic pain. It is obvious that there is a tremendous clinical potential for tapping into this peripheral opioidergic system with the help of peripherally acting opioid receptor agonists. In the last years, there has been a steady stream of research dedicated to develop peripherally restricted opioid receptor agonist molecules for this purpose. As of date, there are no specifically approved peripherally restricted opioid molecules available solely for peripheral analgesic application. The great deal of interest in this area has prompted us to review some of the ongoing efforts in this direction. Peripherally restricted exogenous kappa-opioid receptor agonists Unlike MOR agonists, KOR agonists did not induce euphoria/addiction, respiratory depression, 59

6 Figure 2. Migration of opioid-producing immune cells and opioid secretion in inflamed tissue. Endogenous opioids (OP) are produced by immune cells in circulation. During tissue inflammation, L- and P-selectins mediate rolling of opioid-containing immune cells along capillary wall in the inflamed tissue, and cell adhesion molecules (ICAM-1 and PECAM-1) mediate their firm adhesion and diapedesis. These cells also express receptors for interleukin-1 (IL-1R) and corticotrophin-releasing hormone (CRHR). During stress or inflammation, there is increased IL-1 and CRH, which activate their respective receptors. This in turn elicits OP release by these cells. OP, or exogenous peripheral opioids (EO), then activates the peripheral opioid receptors expressed by primary afferent neurons (see Figure 1), resulting in peripherally mediated analgesia. Reprinted with permission from Macmillan Publishers Ltd. 34 or gastrointestinal transit inhibition. Therefore, they were viewed as an attractive alternative for designing potent and safer analgesics. Three generations of kappa-agonists have been studied so far. The-first generation KOR agonists included spiradoline and enadoline. 54,55 These KOR agonists were small molecules, orally active, and able to penetrate the brain. They lacked side effects similar to that seen with morphine, at the same time being effective clinically. 56 Further study showed that the side effects that were seen were sedation and euphoria, neuropsychiatric effects leading to the discontinuation of its development any further. 56,57 The neuropsychiatric effects were thought to be due to the KORs inhibiting dopamine release. 58,59 The second generation of peripheral KOR agonists was chemically related to the first generation of kappa-agonists but more peripherally selective. This generation of peripheral KOR agonists also composed of orally active small molecules, a major example being EMD61753, also known as asimadoline. 60 Unfortunately, the advantage of asimadoline being more peripherally restricted than the earlier drugs was offset by its lack of analgesic efficacy at permissible doses. 60 Although largely abandoned in its pursuit as a peripheral opioid analgesic, asimadoline still has a potential role in the treatment of certain gastrointestinal disorders, notably irritable bowel syndrome (IBS). 61 Departing from the previous line of development, the third generation of peripheral KOR agonists was based on injectable (nonoral) peptides because of their hydrophilic property and hence relative lack of penetration of the blood-brain barrier. Following an initial lead, 62 the group closed in on a D-amino acid tetrapeptide and similar compounds with improved in vivo characteristics. 66 These new D- amino acid tetrapeptide analogs have undergone extensive preclinical testing for receptor selectivity profile, peripheral restriction, and antinociceptive activity. Of this class of compounds, two have shown particular promise: FE and FE These two compounds were shown to be peripherally selective KOR agonists with analgesic and antiinflammatory properties. 48 FE and FE showed high affinity, selectivity, and agonist action for human KOR-1. They also demonstrated peripherally mediated analgesia in several animal pain models along with a wide therapeutic window, indicating a good safety profile. 67 FE200665, now known as CR665, has been studied in humans and a report has been published recently. 68 The authors studied the analgesic efficacy of intravenous CR665 in several cutaneous, deep somatic, and visceral experimental pain models in healthy male volunteers and compared it with placebo and oxycodone. While oxycodone produced significant pain relief in all the models, CR665 produced significant analgesic effect only on visceral pain (esophageal distension). It was not useful in the somatic pain models. Indeed, it actually paradoxically decreased the pain tolerance threshold to cutaneous pain. Thus, although promising at the animal and preclinical levels, KOR agonists need more studies at the clinical level to demonstrate their efficacy. Their effects on gastroenterological symptoms of pain and distension, however, have been more noteworthy, as demonstrated by CR and also by fedotozine, ADL , and asimadoline. Hence, the following section discusses the potential application of peripheral KOR agonists in visceral pain. 60

7 Peripheral KOR agonists: Potential application in visceral pain Fedotozine was the first compound with KOR agonist activity to be evaluated for visceral pain in a clinical setting. The compound was found to be superior to placebo in reducing abdominal pain and bloating in nonulcer dyspepsia 69 and IBS. 35 It also increased pain perception thresholds associated with colonic distension in patients with IBS. 70 Fedotozine is an atypical KOR agonist with mixed kappa-/mu-opioid activity, 71 with a high affinity for the k1a-binding site. 72 More recently, a pilot study reported that the KOR agonist, ADL , was effective in reducing pain in patients suffering from chronic pancreatitis. 73 ADL is a classical k1/kor1-selective agonist with peripheral selectivity. The analgesic response appeared to be robust and was not associated with the central side effects of brain-penetrating KOR agonists such as pentazocine, suggesting that ADL did not reach the brain, which therefore supported that the effects of ADL were mediated peripherally. The onset of analgesia was immediate, reaching a plateau within 60 minutes, and remaining at maximal levels for the duration of the monitoring period (4 hours). During this time interval, the plasma levels of the compound are estimated to have ranged from high nanomolar (first-hour, during and after administration) to intermediate/low nanomolar levels (B100 nm or less, 3rd and 4th hours). The plasma levels were perfectly suitable to activate k1-receptors but were probably too low to elicit a nonspecific sodium channel blockade, at least during the last 2 hours of the study, when visceral analgesia was still maximal. Despite these preliminary and encouraging results, more definitive clinical proof of concept for the therapeutic relevance of peripheral k1-receptors in visceral pain is needed. After the failure of asimadoline 61 to produce pain relief in clinical samples of patients undergoing knee surgery, 26 research interest turned toward asimadoline in visceral (especially abdominal) pain and discomfort. 61 Delvaux et al. 74 compared the effect of a single oral dose of asimadoline 0.5 mg versus placebo on sensory thresholds and colonic compliance in 20 female patients with IBS in a randomized double-blind crossover trial. Asimadoline decreased the overall perception of pain over a wide range of pressure distension of the colon while maintaining its compliance. In contrast, in a clinical trial of 100 patients with IBS, 75 average pain 2 hours after on-demand treatment with asimadoline was not significantly reduced when compared with placebo. However, posthoc analyses suggested that asimadoline was effective in reducing abdominal pain in the mixed subtype of IBS but not in the diarrhea-predominant subtype. Finally, in a recent 12-week double-blind, randomized, multidose, placebo-controlled trial in 596 patients with IBS, 76 there was no significant improvement on the primary endpoint (number of months of adequate relief of IBS pain or discomfort). However, in the diarrhea-predominant subtype of patients with IBS with at least baseline moderate pain, asimadoline (0.5 mg) produced significant improvement on a number of secondary outcome measures such as adequate relief of IBS symptoms, pain scores, pain free days, urgency, and stool frequency. Thus, the results of this large study contradicted the previous study results regarding the efficacy of asimadoline in the specific subtype of IBS. In conclusion, although the jury is still out in this matter, asimadoline warrants further evaluation as a possible treatment for IBS because it has been well tolerated in human trials to date, with promising but inconsistent efficacy. Peripherally restricted exogenous delta-opioid receptor agonists No drug in this class has yet reached even the level of preclinical studies. However, two recent studies have focused our attention on the potential importance of developing such peripherally restricted DOR agonists. Kabli and Cahill 77 studied the role of DOR and its agonist, deltorphin-ii, in a rat model of neuropathic pain and allodynia. Deltorphin-II increased the pain threshold produced by peripheral nerve injury. Western blotting techniques indicated that there may be a bilateral increase in the expression of DOR following peripheral nerve injury. Immunohistochemical studies confirmed upregulation in dorsal root ganglia neurons in neuropathic pain when compared with control animals. The authors noted that these findings suggest that peripheral DORs may be an attractive therapeutic target in the treatment of neuropathic pain. In a second publication, Obara et al. 78 investigated the efficacy of local intraplantar injection of peptide and nonpeptide MOR, DOR, and KOR agonists in rat 61

8 models of inflammatory and neuropathic pain. Using two different pain models for inflammatory and neuropathic pain, the authors showed that while the ED50 dose range of MOR and KOR agonists required to induce analgesia in neuropathic pain was much higher (5-12 times) than the ED50 for inflammatory pain, only DOR agonists were effective in the same dose range in both the pain models. Thus, the potent antinociceptive effects of DOR agonists point to the peripheral DOR as an interesting target in searching for new peripherally active analgesics for chronic pain therapy, especially in neuropathic pain. This pathway is of particular interest as neuropathy observed in patients is often coupled with inflammatory features 78 and opioids can act through the opioid receptors present on immune cells (eg, macrophages), which migrate to the inflamed/injured tissue. Peripherally restricted exogenous mu-opioid receptor agonists Three broad strategies have been pursued to demonstrate the beneficial effects of MOR agonists in the control of pain peripherally. The first is the use of centrally active agonists (the prototype being morphine) in peripheral locations for peripheral opioid action. The second is the oral or systemic use of an MOR agonist that does not cross the blood-brain barrier. The best example of this class is loperamide. The third is the development of specific compounds with peripheral and selective MOR agonist action. It is now well established that even systemically administered opioids can have an appreciable part of their analgesic effects by acting on peripheral opioid receptors. Several studies indicate that a large proportion (about percent) of the analgesic effects produced by systemically administered opioids can be mediated by peripheral opioid receptors. In addition, human studies have shown that opioid agonists that do not readily cross the blood-brain barrier are beneficial in patients with neuropathic and visceral pain 79 and that opioid agonists can have the same analgesic efficacy as conventional opioids. 80 Many of these effects are mediated by peripheral MOR, though peripheral KOR and DOR are also involved. 81 One of the best-documented uses of the first strategy mentioned earlier is the use of morphine intra-articularly after knee surgery. Starting from the influential first double-blind randomized controlled trial (RCT) published by Stein et al., 82 there are more than 60 published studies of varying designs and quality focused on this theme. A qualitative systematic review of 36 RCTs found that despite significant problems in design, data collection, statistical analysis, and reporting, IA morphine may have some effect in reducing postoperative pain intensity and consumption of analgesics. 83 Of these six studies that compared IA morphine with intravenous or intramuscular morphine or with IA saline without a bupivacaine control, four showed greater efficacy with IA morphine. A later meta-analysis 84 quantitatively analyzed 19 studies suitable for meta-analysis and found that there was an improvement in analgesia after morphine when compared with placebo in the order of mm decrease on the Visual Analogue Scale during all three phases (early, 0-2 hours postoperative, middle, 2-6 hours, and late, 6-24 hours) of treatment. However, the authors did not find any clear-cut doseresponse effect and could not entirely rule out systemic effect of morphine. Another later systematic review by the earlier group 85 found that IA morphine works best when the initial pain level is appreciable, ie, at least 30 percent of the maximum possible pain intensity. In their meta-analysis, the analysis of sensitive studies indicated that 5 mg of IA morphine injected into the knee joint provides postoperative pain relief for up to 24 hours. Morphine or other opioids have also been used locally for their peripheral effects in a variety of other settings. Likar et al. 86 demonstrated analgesic efficacy of opioid injected into the knees of patients with osteoarthritis who did not undergo surgery. The same group also demonstrated that morphine added to local anesthetic for submucosal infiltration in dental surgery improved postoperative analgesia lasting for up to 24 hours. 87 Applying the second strategy, eg, using loperamide, an MOR agonist that does not cross the blood-brain barrier and therefore lacks central effects after systemic administration, Guan et al. 88 studied the efficacy of loperamide in rat models of neuropathic pain. Subcutaneous loperamide dose-dependently reversed the mechanical allodynia. This antiallodynic effect produced by systemic loperamide was shown to be specific to peripheral MOR action by a series of experiments. The findings suggested that loperamide could effectively attenuate neuropathic pain, primarily through activation of peripheral MORs in local tissue. It is, however, interesting to note that the antihyperalgesic effects of loperamide is also partly explained by its action on peripheral DORs as recently shown by Shinoda et al

9 A recent small open clinical observation was reported from Japan on four patients suffering from pain because of chronic graft-versus-host disease who were treated with a loperamide oral-rinse solution. 90 Two-week continued use of the drug solution improved not only the pain scores but also the pain-causing disabilities associated with eating, drinking, and sleeping, with no noticeable side effects. Current results suggest that the MOR agonist loperamide has a potential analgesic effect that could be clinically useful as a peripheral analgesic agent for stomatitis pain. However, these observations will need to be further confirmed in a RCT. Another potent analgesic with MOR effects is frakefamide (FF). 91 It is thought to act only on peripheral opioid receptors not crossing the bloodbrain barrier freely because of its large size (molar mass g). Modalen et al. 91 showed that during resting ventilation, FF did not cause central respiratory depression like morphine, which is the most feared side effect of opioid administration. 92 In this study, it was shown that FF lacks depressive effects on the central nervous system. An interesting observation was that all patients who received FF experienced a myalgia like pain that came on within 15 minutes of starting the FF infusion and disappeared within 30 minutes following the start of the infusion. The mechanism of this myalgia is unknown. More work needs to be done to assess if FF a peripherally acting opioid agonist without the side effect of respiratory depression can produce analgesia comparable with that produced by morphine in humans. Peripheral opioid agonists in animal models A few peripherally selective MOR or mu-dor agonists have been studied only in animal models with interesting results. These, of course, have to be studied extensively further to assess the safety and applicability in humans. The following section has the recent update on these peripheral agonists that have been found to be successful in animals and have not yet been proved to be effective in clinical studies. H (2) N-Tyr-D-Thr-Gly-Phe-Leu-Ser-(O- -D-lactose)-CONH (2) (MMP2200) is a novel glycopeptide opioid agonist with similar affinities for mu- and delta-receptors. A recent study by Do Carmo et al. 93 demonstrated antiallodynamic effect of this compound in four experiments on rhesus monkeys, suggesting that systemically administered MMP2200 acted as a peripheral, mu-/delta-opioid agonist with limited distribution to the central nervous system. Whiteside et al. 94 described the in vivo pharmacological properties of the structurally novel, highly potent, systemically available yet peripherally restricted mu-opioid agonist, [8-(3,3-diphenyl- propyl)-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3- yl]-acetic acid (DiPOA). DiPOA administered intraperitoneally produced naltrexone-sensitive, dose-dependent reversal of Freund s complete adjuvant-induced inflammatory mechanical hyperalgesia (1-10 mg/kg). It was not antihyperalgesic in the Seltzer model 95 of neuropathic pain. This was the first report of a peripherally restricted, small-molecule mu-opioid agonist that is nonsedating, antihyperalgesic, and effective against inflammatory and postsurgical pain when administered systemically. Similarly, Bileviciute-Ljungar et al. 96 investigated peripherally mediated antinociception produced by the MOR agonist 2-[(4,5alpha-epoxy-3-hydroxy- 14beta-methoxy-17-methylmorphinan-6betayl)amino]acetic acid (HS-731) after subcutaneous and oral administration in rats with carrageenaninduced hindpaw inflammation. Their results show that systemic (subcutaneous and oral) treatment with HS-731 produces potent and long-lasting antinociception through peripheral mechanisms in rats with carrageenan-induced hind paw inflammation. FUTURE RESEARCH Future research suggested to enhance peripheral opioid analgesia is summarized in Table 1. The first task is to develop opioids with virtually no central component of action. As discussed earlier in the KOR agonist section, this can be a time-consuming and daunting task, but not impossible. The second strategy is to develop peripherally restricted opioids with analgesic, anti-inflammatory, and neuropathic pain. The study by Obara et al. 78 in which the efficacy of peripheral DOR agonists to attenuate both inflammatory and neuropathic pain at the same dose is shown indicates the potential usefulness of this strategy. Delineating the differential receptor specificity profiles of such drugs is also important in this regard. The other group of futuristic strategies could consider boosting the production, transport, or release of endogenous opioids by leucocytes and other peripheral immune cells in response to inflammation or neuropathic damage, decreasing the degradation and/or removal of such opioids from the peripheral 63

10 Table 1. Various ways to enhance peripheral opioid analgesia: A futuristic approach 1. Develop opioids with near-zero central component of action. 2. Develop peripheral opioids with both analgesic and anti-inflammatory action. 3. Develop opioids with analgesic efficacy in both inflammatory and neuropathic pain. 4. Delineate differential action profiles of opioids acting on peripheral mu-, kappa-, and delta-receptors. 5. Boost the production, transport, or release of endogenous opioids by leucocytes and other peripheral immune cells in response to inflammation or neuropathic damage. 6. Decrease the degradation and/or removal of such opioids from the peripheral site of action. 7. Enhance the production, axonal transport, or efficacy of peripheral opioid receptors by the peripheral pain-sensory neurons in response to inflammation or neuropathic damage. 8. Develop molecules with action on peripheral systems that enhance the peripheral opioid system, such as the peripheral cannabinoid receptors, chemokine system, and peripheral adrenergic system. 9. Focus on the role of peripheral endogenous opioids in production and maintenance of neuropathic pain and in development of appropriate targets. 10. Develop gene therapy targeted at increased production of peripheral opioid ligands or opioid receptors. site of action, and enhancing the production, axonal transport, or efficacy of peripheral opioid receptors by the peripheral pain-sensory neurons in response to inflammation or neuropathic damage. Targeting other systems that interact with the peripheral opioid system (eg, the peripheral cannabinoid receptors, 97 chemokine system, 98 and peripheral adrenergic system 99 ) could be yet another potentially fruitful strategy. Last but not the least, the use of targeted gene therapy to enhance the production of peripheral opioid ligands 100 or opioid receptors, 101,102 although at a basic research level currently, may hold promise for the future. CONCLUSIONS Recent research has shown that opioid antinociception can occur in the periphery in addition to the central nervous system. Peripheral opioid receptors present on sensory nerves mediate analgesic effects when binding with peripheral opioid receptors occurs. This is especially seen in the presence of inflammation when the peripheral opioid receptors are upregulated and local immune cells express endogenous opioids. Other substances such as CRH, cytokines released in the presence of inflammation, and environmental stimuli can also release opioid peptides producing analgesia. There is also a close relationship between peripheral analgesia and the immune system and the release of excitatory peptides. Peripheral opioid agonists cause analgesia by inhibiting the excitability of sensory nerves or inhibiting the release of excitatory, proinflammatory peptides. The obvious theoretical advantage of using these molecules is that analgesia is achieved while avoiding the bothersome-to-dangerous centrally mediated adverse effects of centrally acting opioids. Molecules known for their central action (eg, morphine) have been used in peripheral tissues (joints, bone, teeth) with reasonable but varied success. Over the last years, several molecules with peripherally restricted opioid agonist activity have been developed and several are in the clinical pipeline. Although none is available as an approved medication to date, a few (eg, the peripherally restricted kappa-agonist FE200665, also known as CR665) have completed phase I and phase II clinical trials and a recent report has been published in humans. 68 Others such as loperamide, which is currently approved for use only as an antidiarrheal agent, have been found to be variably useful as a peripherally acting opioid analgesic. A number of research are currently underway, and this is an exciting area for both basic and applied clinical research. There is also a great potential for even further research in several other areas with regard to peripheral opioid 64

11 agonists. This would include the development of peripheral opioids with almost no central component of action, peripheral opioids with both analgesic and anti-inflammatory action, opioids with differential action profiles on mu-, kappa-, and deltareceptors as well as boosting the production, transport, and release of endogenous opioids by leucocytes and peripheral immune cells in response to inflammation or neuropathic damage. Other potential areas of new research will be to decrease the degradation of peripheral opioids, to enhance the production and efficacy of peripheral opioid receptors as well as gene therapy targeting the increased production of peripheral opioid receptor ligands. Nalini Vadivelu, MD, Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut. Sukanya Mitra, MD, Department of Anaesthesia and Intensive Care, Government Medical College and Hospital, Chandigarh, India. Roberta L. 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