Peripheral Opioid Analgesia: Clinical Applications Jochen Oeltjenbruns, MD and Michael Schäfer, MD*

Address *Department of Anaesthesiology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany. E-mail: [email protected] Current Pain and Headache Reports 2005, 9:36–44 Current Science Inc. ISSN 1531-3433 Copyright © 2005 by Current Science Inc.

Peripheral opioid analgesia is undoubtedly of clinical relevance, especially considering that systemic opioid therapy often is hampered by central side effects. Despite some clinical studies that do not show peripheral opioid-mediated pain control, mostly because of methodologic shortcomings, studies evaluating inflammatory pain conditions show clear evidence and the number and the sites of applications are increasing. The intention of this paper is to give insight into the recent experience with the clinical applications of peripheral opioid analgesia.

Introduction Peripheral opioid analgesia is clinically relevant because it lacks the opioid-typical, therapy-limiting side effects such as respiratory depression, sedation, nausea, constipation, addiction, and tolerance [1]. In addition, the local application of analgesics allows (compared with systemic administration) optimization of drug concentrations at the site of pain origin without the need to titrate doses into a therapeutic range to avoid drug side effects. An increasing number of agents, partly never thought to act locally, are studied for their potential to produce peripheral analgesia [2•]. Although there are historic reports about peripheral opioid analgesia for painful hemorrhoids [3] and neuralgia [4,5], opioid analgesic effects long have been thought to occur exclusively within the central nervous system. Since 1980, there has been an increasing number of reports about the action of opioids in peripheral tissue. In 1991, the first clinical trial showed a peripheral analgesic effect for intra-articular morphine in patients undergoing arthroscopic knee surgery [6,7]. This new concept of pain control in peripheral tissue by opioids [8] has been extensively investigated in the following years with several new findings in experimental and clinical studies. Peripheral opioid receptors of all three types (µ-, δ- and κ-) have been identified on small to medium size neuronal

cell bodies within dorsal root ganglia. They are axonally transported to central and peripheral nerve terminals of primary afferent neurons (A- and C-fibers). Sympathetic postganglionic neurons and immune cells also can express opioid receptors, but their role in the modulation of pain still is unclear. The pharmacologic characteristics of these peripheral opioid receptors are very similar to those within the brain. Receptor activation by opioids results in an attenuated excitability and a decreased propagation of action potentials within peripheral sensory neurons. These effects are elicited by opioid receptor-coupled G-proteins, leading to inhibition of cyclic adenosine monophosphate, increased potassium efflux, decreased calcium entry, inhibition of tetrodotoxin-resistant sodium currents, and inhibition of calcium-dependent release of pronociceptive, proinflammatory neuropeptides (eg, substance P). In addition to the inhibition of pain, peripherally applied opioids also may elicit anti-inflammatory effects by inhibition of neurogenic inflammation and suppression of leukocyte function by acting on opioid receptors of immunocytes [9••]. Peripheral endogenous opioid peptides, the natural ligands for µ- (endorphins, enkephalins), δ- (enkephalins, endorphins), and κ-opioid receptors (dynorphin) have been detected within immune cells (lymphocytes, monocytes, macrophages, and granulocytes). The secretion of these opioid peptides is stimulated by environmental stress, cytokines, and releasing agents such as corticotropin-releasing hormone and adrenergic agonists. Other sources of peripheral opioids are the adrenals and the pituitary gland, but these are not the sources for opioid ligands at peripheral opioid receptors [9••]. New selective µ opioid receptor agonists, the endomorphins, have been isolated from immune cells and there are hints of them also being involved in the peripheral control of inflammatory pain [10]. Tissue injury, mainly inflammation, is the prerequisite for sufficient (endogenous and exogenous) peripheral opioid analgesia. The synthesis, axonal transport, and expression of opioid receptors are enhanced, leading to improved agonist efficacy at peripheral nerve terminals. Owing to the specific local milieu (eg, low pH) of inflamed tissue, preexistent inactive opioid receptors are rendered active, disruption of the perineurium enhances diffusion of opioids to the receptors, enhanced sensory nerve terminal “sprouting” increases the number of peripheral opioid receptors, and G-proteins bind more efficiently to peripheral opioid receptors [9••]. All of these mechanisms result in higher

Peripheral Opioid Analgesia: Clinical Applications • Oeltjenbruns and Schäfer

opioid efficacy and better pain control. In parallel, migration or extravasation of opioid-containing immunocytes into inflamed tissue increases the presence of endogenous ligands for peripheral opioid receptors. Following certain stimuli, these opioids can be released to contribute to endogenous attenuation of pain [11,12]. There is an increasing number of clinical studies demonstrating the analgesic efficacy of locally applied exogenous opioids in patients [9••,13–16]. However, several clinical studies did not detect peripheral analgesic effects of locally administered opioids [14,17]. Most of these studies used noninflamed conditions, insufficient pain intensity, inadequate controls, small sample sizes, inadequately low doses, and prolonged effects of anesthetic drugs in the perioperative setting [9••,14–16,18••]. This article does not review all of the literature available on each of these clinical applications, but rather focuses on published clinical studies and case report series of the past years, which have extended the concept of peripheral opioid analgesia.

Clinical Applications Intra-articular administration Since Stein et al. [6] demonstrated in the first clinical trial in 1991 that administration of morphine into the knee joint after arthroscopic surgery produced a significant naloxonereversible analgesic effect, a large number of clinical studies followed to investigate the benefit of intra-articular morphine. In several systematic reviews, it was shown that most of these studies confirmed the initial benefit of intra-articular morphine for postoperative pain relief [15,16,18••]. However, there also were studies with controversial results. It was described in these reviews that differences may be caused partly by methodologic shortcomings such as a lack of sensitivity as a result of low pain intensity following minor arthroscopic procedures, prolonged perioperative anesthetic effects, a lack of positive and negative controls, and various degrees of the local inflammatory response. Overall, there is good evidence for postoperative pain relief for up to 24 hours when adequate doses of intra-articular morphine are administered (3–5 mg) after knee surgery. Marchal et al. [19] assessed the different analgesic responses to intra-articular morphine, bupivacaine, and placebo in two different types of arthroscopic knee surgery under general anesthesia. Patients were grouped according to the degree of intra-articular damage into the low inflammatory surgery group (diagnostic arthroscopies, partial meniscectomy) and the high inflammatory surgery group (synovial plica removal, patellar shaving, lateral retinacular release, and anterior cruciate ligament reconstruction). Both groups received 25-mL bupivacaine 0.25%, 5-mg morphine in 25 mL of saline, or 25 mL of saline 0.9% alone (placebo). Patients in the low inflammatory surgery group showed the highest benefit regarding postoperative pain relief at 4 and 8 hours when they received intra-articu-

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lar bupivacaine. Patients in the high inflammatory surgery group receiving intra-articular morphine showed the lowest postoperative pain intensity scores at 24 hours and had significantly fewer requirements for rescue analgesics. Thus, the authors concluded that intra-articular bupivacaine or intra-articular morphine should be differentially administered with regard to the type of arthroscopic surgery. In a clinical trial by Akinci et al. [20], which examined the analgesic effects of intra-articular morphine, tramadol, or saline in 75 patients with arthroscopic knee surgery, the postoperative reduction in pain intensity was observed in the intra-articular morphine and tramadol groups compared with the saline-treated control group. Pain relief as a result of local opioid treatment was more pronounced in a subgroup of patients who experienced knee pain over more than 6 months. In a recently published clinical study, Likar et al. [21] examined whether the number of inflammatory cells within the synovial tissue had any influence on the dosedependent analgesic effects of intra-articular morphine. Two hundred patients undergoing arthroscopic knee surgery were randomly assigned to receive intra-articular saline or 1, 2, or 4 mg of morphine. The results confirmed previously demonstrated dose-dependency of intra-articular morphine analgesia [22•], but by the time to first analgesic request and the total amount of rescue analgesic consumption, not by postoperative visual analog scale (VAS) scores [21]. Synovial specimens were taken from each patient, who were subgrouped into those with more and those with less than the median number of inflammatory cells/mm2. Although dose-dependent analgesic effects of intra-articular morphine could be shown for both subgroups, there was neither a significant left- nor rightward shift in the dose-response curve. A leftward shift could have been interpreted as a potentiation of intra-articular morphine analgesia following increasing numbers of inflammatory cells, and a rightward shift as the development of tolerance as a result of numerous inflammatory cells, which contained endogenous opioid peptides that may produce cross-tolerance to morphine. However, neither was the case for several reasons, including less controlled inflammatory conditions, less sensitivity because of relatively low pain intensity, and greater variability of pain measurements in patients than in animal studies. The lack of development of tolerance is an interesting finding in the sense that repetitive administrations of opioids less likely may result in a loss of analgesic efficacy. In a parallel-group, double-blind study with 90 patients undergoing knee arthroscopy in a post-hoc subgroup analysis of patients with higher postoperative pain intensity (VAS > 10 mm), Rosseland et al. [23] showed that these patients (n = 28) had significantly lower pain intensity and less analgesic rescue medication with intra-articular morphine than placebo. Patients with very low pain intensity as a result of the local anesthetic effect did not show any benefit of intra-articular morphine. To verify this

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observation, the same author performed an interesting study with 57 patients who underwent knee arthroscopy under general anesthesia and received a soft intra-articular catheter for postoperative pain management [24]. Only those 40 patients (70%) were included who developed moderate to severe postoperative pain within 1 hour after surgery. In this group, patients received 10 mL of saline or 10 mL of saline with 2 mg of morphine. Surprisingly, this study showed a significant pain reduction and consumption of rescue analgesics in both groups. The authors interpret their results in a way that the intra-articular instillation of saline already has a pain-relieving effect. However, this is in contrast to studies showing a dose-dependent analgesic effect of intra-articular morphine. There may be hints that intra-articular morphine administered preoperatively has a pre-emptive analgesic effect [25]. Reuben et al. [25] observed 40 patients undergoing ambulatory arthroscopic meniscectomy of the knee under local anesthesia and intravenous (IV) sedation with midazolam and propofol. One group received intra-articular morphine 3 mg with 30 mL intra-articular bupivacaine 0.25% 30 minutes before surgery; the other group received the same morphine dose with 30 mL intra-articular bupivacaine 0.25% at the end of surgery. The first group experienced a significantly longer time interval without taking rescue analgesics and consumed significantly fewer rescue analgesics. Thus, the authors concluded that intra-articular morphine administered preoperatively had a pre-emptive analgesic effect in arthroscopic meniscectomy. Further attempts to ameliorate the intra-articular morphine analgesic effect were made by co-administrating intraarticular clonidine, suggesting a synergistic effect as seen in animal models [26]. Joshi et al. [27] observed 60 patients undergoing arthroscopic meniscectomy under local anesthesia with 30 mL intra-articular bupivacaine 0.25% and IV sedation with propofol and midazolam. Patients receiving the combination of intra-articular morphine 3 mg and intraarticular clonidine 1 µg/kg showed a significantly longer time to first analgesic request, less total consumption of rescue analgesics, and lower pain scores at rest and movement postoperatively compared with patients receiving only intra-articular morphine 3 mg or intra-articular clonidine 1 µg/kg. Similar, but less obvious results were seen by Buerkle et al. [28], who observed 50 patients undergoing therapeutic arthroscopic knee surgery under general anesthesia and performed postoperative analgesia by intra-articular morphine 1 mg or intra-articular clonidine 150 µg or the combination of both analgesics. There are two interesting studies performed by Rasmussen et al. [29,30•], who studied the influence of postoperative intra-articular morphine analgesia on the duration of convalescence (return to work) following arthroscopic meniscectomy and diagnostic knee arthroscopy. Both studies showed that intra-articular morphine 4 mg added to intra-articular bupivacaine 150 mg significantly reduced postoperative pain intensity and enhanced the return to work. The study per-

formed by Kligman et al. [31] assessed different techniques of intra-articular morphine applications. Sixty patients undergoing arthroscopic meniscectomy under local anesthesia with 10 mL intra-articular bupivacaine 0.5% were randomized to receive 1 mg of morphine or saline injected into the synovial tissue/the outer third of the meniscus following meniscectomy or into the articular cavity. At the end of surgery, patients received saline or 1 mg morphine into the intra-articular cavity. Patients who received morphine into the synovial tissue/ the outer third of the meniscus showed significantly lower pain intensity scores and less consumption of rescue analgesics postoperatively than patients who received 1 mg of morphine into the intra-articular cavity. A limitation of this study is that pain scores were quite low in both groups because of the local anesthetic effect. In chronic pain states such as rheumatoid and osteoarthritis, intra-articular morphine injections elicited pain relief of longer duration (up to 7 days) [32,33]. This may be the result of analgesic and anti-inflammatory effects of locally applied opioids. Likar et al. [32] could show that a single dose of 1-mg intra-articular morphine into the knee joint of patients with chronic osteoarthritis resulted in a significant reduction in pain intensity at rest and during movement with a longlasting effect up to 1 week. Similar results were seen by Stein et al. [33] who were treating patients with rheumatoid arthritis or osteoarthritis. Patients received a single dose of 3-mg intra-articular morphine, 4-mg intra-articular dexamethasone, or intra-articular saline. Whereas saline attenuated arthritic pain only moderately and for a short time, dexamethasone reduced arthritic pain intensity significantly in a delayed fashion consistent with a pure antiinflammatory effect. In contrast, intra-articular morphine showed an immediate significant analgesic effect, most likely because of the inhibition of pain transmission. However, the analgesic effect persisted for up to 7 days, which cannot be explained by an inhibition of pain, but rather by possible anti-inflammatory effects similar to dexamethasone. This explanation was substantiated by the fact that the synovial leukocyte count was significantly reduced after intra-articular morphine [33]. The demonstrated analgesic and anti-inflammatory effects of intra-articular morphine in patients with chronic arthritis eventually could be an alternative to standard treatments such as intra-articular dexamethasone because it is lacking serious side effects such as cartilage breakdown [34]. However, this needs to be corroborated by future clinical trials that also should investigate repeated intra-articular morphine treatments in comparison with standard intra-articular dexamethasone. Attempts have been made to transfer the experiences of intra-articular analgesia in the knee joint to intra-articular and subacromial/intrabursal application of opioids in the shoulder. Intra-articular injection of morphine (1 mg, but neither fentanyl nor sufentanil) plus bupivacaine 0.25% (20 mL) into the humeral joint after open rotator cuff repair resulted in significantly lower pain scores and less

Peripheral Opioid Analgesia: Clinical Applications • Oeltjenbruns and Schäfer

consumption of rescue analgesics at 4, 6, and 8 hours postoperatively [35]. However, the small number of patients, the lack of a placebo control, and the low baseline pain intensity influenced the results. Further studies are recommended to prove these findings. Administration of opioids into the subacromial space for postoperative analgesia in shoulder surgery offers conflicting results. Henn et al. [36] and Scoggin et al. [37] did not find any significant benefit of 5-mg morphine regarding postoperative pain relief; however, Muittari and Kirvelä [38] reported on a lower consumption of rescue analgesics in patients with intrabursal administration of 5-mg oxycodone at the end of open shoulder surgery. The continuous intrabursal infusion of morphine plus bupivacaine (40 mL 0.5% bupivacaine + 8 mg of morphine 0.5 mL/h) through an intrabursal catheter seemed to provide better analgesia and less consumption of rescue analgesics compared with a saline-treated control group. Compared with the knee joint, the shoulder is much more complex and arthroscopic evaluation of the shoulder may include a trauma for the gleno-humeral joint and the subacromial space, distinct compartments that normally do not communicate. The subacromial space itself is not a closed cavity; even the histologic conditions are different to the knee. Thus, further studies are needed to evaluate the benefit of intra-articular morphine in shoulder surgery. Evaluating the efficacy of intra-articular morphine in the management of temporomandibular joint pain, Furst et al. [39] observed patients with internal disc derangements of the temporomandibular joint and persisting pain states. Patients were undergoing a therapeutic unilateral temporomandibular joint arthroscopy and received intra-articular injections of saline, morphine, bupivacaine, or morphine plus bupivacaine at the end of the procedure. The authors found significantly lower pain scores compared with placebo in patients receiving 1 mL of morphine 0.2% intra-articular at 4, 8, and 12 hours postoperatively. Despite a higher effectiveness of intra-articular bupivacaine (2 mL 0.5%) at 24 hours, intra-articular morphine appeared to have a prolonged analgesic effect.

Peridental administration In contrast to some controversial results in intra-articular opioid analgesia, the peridental injection of opioids shows more conformity. The submucous injection of 1 mg of morphine adjuvant to the local anesthetic (articaine) for infiltration anesthesia shows significant analgesic effects from 8 to 24 hours (when the local anesthetic effect subsides) [40]. Patients treated with morphine had lower pain intensity scores and less consumption of rescue analgesics compared with placebo. This was seen only in patients who were submitted to the hospital with severe inflammatory tooth pain, but not in patients who were scheduled for elective dental surgery [41•]. This seems to be consistent with experimental studies that emphasize the presence of

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an inflammatory response for best peripheral opioid effects. In addition, when 1 mg of morphine was administered perineurally (mandibular nerve) in patients with inflammatory tooth pain, it was not effective in relieving postoperative pain, suggesting that opioid receptors only at the peripheral nerve terminals, but not along the axon, seem to be an adequate target for local analgesic effects of opioid [40,41•]. Dionne et al. [42] confirmed these results in showing that low doses of morphine (0.4, 1.2, and 3.6 mg) administered into the intraligamentary space of a chronically inflamed hyperalgesic tooth produced a doserelated naloxone-reversible analgesia. The repeated topical applications of morphine plus lidocaine (local spray) did not show better pain relief than topical applications of lidocaine alone in patients undergoing elective dental surgery. Similar to the previous findings, topical morphine was not effective in patients without inflammation and pain before surgery [43]. Thus, local administration of opioids for dental pain models showed evidence for significant pain relief only under inflammatory conditions.

Topical wound infiltration As reviewed by Moiniche et al. [44], incisional local anesthesia for postoperative pain relief after abdominal surgery showed a lack of evidence, except for herniotomy. Recent studies were undertaken to evaluate the analgesic effects of incisional local opioid-analgesia for postoperative pain control. Rosenstock et al. [45] could not find significantly improved postoperative analgesia for up to 7 days postoperatively when 5 mg of morphine (6-mL solution) was administered incisionally in comparison with IV or intramuscular (IM) 5-mg morphine before skin closure at the end of inguinal herniotomy. With additional fentanyl (10 µg) to 10 mL lidocaine 0.5% for wound infiltration, Tverskoy et al. [46] observed significant decreases in spontaneous and movement-associated pain and a prolonged duration of the local anesthetic effect 24 hours postoperatively. However, the perioperative spinal anesthesia and the fixed postoperative meperidine consumption likely would have contaminated the results. Postsurgical wound infiltration after breast surgery under general anesthesia with 0.5 µg/kg fentanyl added to 0.3 mL/kg ropivacaine 0.375% showed no significant reduction in postoperative pain compared with the local anesthetic or IV treatment alone [47]. In a small sample size, Takano et al. [48] found significantly lower pain scores, fewer postoperative consumption of rescue analgesics, and longer time to first analgesic request after spinal surgery when administered 50 µg fentanyl (10 mL) just before wound closure. This effect was similar to infiltration with 10 mL of lidocaine 1% [48]. There also have been attempts in local opioid analgesia for postoperative pain control after ophthalmosurgery. Pterygium patients receiving 4 mg of morphine plus 1.6 mL of lidocaine 1% (2-mL solution) injected peribulbar reported significantly lower pain scores 24 hours after pterygium surgery

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than the patients receiving injections of lidocaine 1% (2 mL) alone [49]. A very interesting and well-performed study by Reuben et al. [50••] investigated local morphine effects in patients undergoing cervical spinal fusion and autologous bone graft harvesting. In this study, former findings in a rat model of local opioid analgesia following osteotomy [51] now could be confirmed in patients. Those patients who were administered 5 mg of morphine into the iliac bone harvest site reported significantly lower pain scores and showed significantly reduced morphine consumption at the harvest site until 24 hours postoperatively when compared with local saline or IM morphine treatment [50••]. The interesting finding of this study was that patients underwent follow-up for 1 year after surgery. When interviewed, 25% them still reported moderate pain at the harvest site. This pain occurred significantly less in patients who were treated locally with 5 mg of morphine. Thus, local opioid treatment may have a long-term benefit in patients, preventing the development of chronic pain states. Local opioid application also showed analgesic effects in a mice model of osteosarcoma-induced hyperalgesia [52]. This may be a possible approach for the treatment of bone cancer pain. The evidence for incisional local opioid analgesia on postoperative pain still remains unclear. As outlined by Moiniche et al. [44], the main problems will be the technique used for administration, the adequate dose (to exclude a fast systemic uptake), and differences in local blood flow. There is evidence that peripheral opioid application likely will contribute to postoperative pain control and to improved wound healing through opioid receptormediated stimulation of the expression of cytokeratin 16, induction of fibroblast proliferation, growth of capillaries, and acceleration of the maturation of granulation tissue and defect epithelialization [53,54]. Therefore, further studies are recommended. Recent studies describe topical opioid treatment of painful skin ulcers, which are a common clinical problem in palliative care. Crossover, placebo-controlled studies performed by Flock [55] and Zeppetella et al. [56] showed significant reduction in pain intensity scores when diamorphine (a 0.1% weight-to-weight mixture of diamorphine and IntraSite gel [Smith & Nephew, London] = 1 mg diamorphine/1mL IntraSite gel) and 10 mg of morphine (10 mg/mL morphine in 8-G IntraSite gel) were applied once daily. In a case series of nine patients by Twillman et al. [57], only one patient did not benefit from a morphine-infused IntraSite gel (a 0.1% weight-toweight solution). This patient’s wound was not open and did not show inflammation. Ribeiro et al. [58] could not find evidence of systemic absorption of morphine (morphine, morphine-6-glucuronide, and morphine-3-glucuronide plasma concentrations were not detected or were too low by high-performance liquid chromatography) in most patients when 10 mg of morphine was administered topically to painful ulcers, suggesting that any analgesic effect of such treatment was

mediated by peripheral mechanisms. Moreover, in a recent case report by Watterson et al. [59], two children with painful dystrophic epidermolysis bullosa received sufficient analgesia by topical treatment with 10-mg morphine sulfate mixed in 15-G of IntraSite gel (0.06%) with an additional healing effect and lack of adverse events. However, limitations of such reports are the small sample sizes and the lack of controlled conditions. Larger, randomized, controlled studies are needed to confirm these results. An interesting study by Peyman et al. [60] demonstrated the analgesic effect of topical morphine in seven patients with unilateral corneal ulcers following intraocular surgery (vitrectomy). Postoperatively, the patients received two eye drops of a 0.5% morphine formulation compared with saline. Topical application of the morphine formulation to the denuded cornea resulted in a considerable pain-relieving effect when pressure was applied to the cornea. The same treatment of the normal contralateral cornea did not produce an analgesic effect at all. In a previous animal model, the author also could show that repeated topical morphine 0.5% had no adverse effects on corneal wound healing. However, these findings are only preliminary data and are limited by the low number of patients. Stiles et al. [61••] and Wenk et al. [62] found no evidence for wound healing disturbances in animals with corneal ulcers treated with morphine solutions. Histologic evaluation of the normal cornea showed numerous δ- and a lower number of µ-opioid receptors in the corneal epithelium and anterior stroma of the cornea. Topical opioid treatment also can be of benefit in mucositis-associated pain. Cerchietti et al. [63,64••] performed two interesting studies in patients with painful chemoradiotherapy-induced oral mucositis receiving a mouthwash of 15-mL 2% morphine solution. By holding this mouthwash for 2 minutes and then swallowing it (repeated every 2–3 hours), the authors found a significant reduction in pain intensity, duration of pain and duration of functional impairment, and a sparing effect of supplemental analgesics. This pain-relieving effect seems to be dosedependent, considering that the 1% morphine solution was not as effective as 2% solution in a dose-response evaluation. The side effects were mild (burning, itching, xerostomia) and probably of peripheral origin because plasma concentrations of morphine measured in five representative patients were negative. Evidence of peripheral antinociceptive effects of opioids in burn injury remains unclear. Studies of healthy volunteers with induced burn lesions treated by subcutaneously administered morphine (2 mg) at the site of injury showed conflicting results in measured heat-pain thresholds and pressure-pain thresholds [65,66]. A recent double-blind, placebo-controlled pilot study performed by Long et al. [67], who treated burn injury patients with morphine-infused silver-sulfadiazine 1% cream (0.01% morphine by weight), showed interesting results. Despite the low number of patients (only four), the results show lower pain intensity rat-

Peripheral Opioid Analgesia: Clinical Applications • Oeltjenbruns and Schäfer

ings and fewer supplemental opioids, suggesting a topical effect of morphine. Although topical application of opioids seems very promising in some cases (eg, mucositis-associated pain), further randomized, controlled clinical trials are needed to substantiate these findings.

Post-thoracotomy pain Interpleural application of opioids for postoperative analgesia after thoracotomy has unclear evidence. Welte et al. [68] could not find superior analgesic effects of continuous interpleural infusion of morphine 0.5 mg/h compared with IV application of the same dose. Respiratory function also was not improved by this application [68]. This is most likely because of the rapid systemic up-take of morphine through the pleural cavity. However, Aykac et al. [69] found a significant reduction in pain intensity scores in post-thoracotomy patients receiving 20 mg of morphine (20-mL solution) in the interpleural cavity compared with the same IV treatment. In addition to the analgesic effect, respiratory function was improved, measured as higher respiratory rates and lower PaCO2 levels. To assess an eventually systemic effect of the interpleural morphine, the authors determined plasma morphine concentrations, which were significantly higher in the IV group. Therefore, intrapleural administration of morphine gives conflicting results and cannot be recommended at this stage. Visceral pain Recent studies investigated the analgesic effect of opioids injected into the peritoneal cavity for postoperative pain control in abdominal surgery. Studies evaluating the peripheral analgesic effect of morphine administered intraperitoneally at the end of laparoscopic cholecystectomy, a widely used technique, showed a lack of evidence. Schulte-Steinberg et al. [70] assessed 1-mg morphine in 20-mL saline injected intraperitoneally and Hernández-Palazón et al. [71] added 2 mg of morphine to 30 mL of bupivacaine 0.25%. Both authors could not find significant analgesic effects measured in pain ratings and supplemental analgesic consumption compared with intraperitoneal bupivacaine 0.25% alone or saline. This is most likely because of the rapid systemic up-take of morphine through the peritoneal cavity. In another placebo-controlled clinical trial, Kalman et al. [72] compared 50 mg of IV morphine with 50 mg of intraperitoneal morphine 30 minutes before laparotomy in 30 patients. Intraperitoneal morphine was significantly less efficacious in reducing postoperative pain than IV morphine. Morphine plasma concentrations were similar in both groups, indicating absorption; however, morphine-6-glucuronide concentrations were higher in the IV group. A recent study performed by O’Hanlon et al. [73] of 100 patients undergoing laparoscopic cholecystectomy showed superior analgesic effects of 1 mg/kg pethidine (maximum, 50 mg) added to 80 mL of bupivacaine 0.125% administered intraperitoneally at the end of laparoscopic cholecystectomy. This was compared with the same dose of pethidine administered intramuscularly and 80 mL of bupivacaine 0.125%

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administered intraperitoneally. There were significantly lower pain scores at rest and upon movement and a significantly lower total dose of supplemental pethidine through patientcontrolled analgesia up to 24 hours after surgery. This superior effect of pethidine compared with morphine may be related to the combination of local anesthetic and opioid analgesic properties. Similar findings were obtained in a study by Colbert et al. [74] in which patients undergoing laparoscopic gynecologic surgery (tubal ligation) received 80 mL of bupivacaine 0.125% intraperitoneally plus 50 mg of pethidine either intraperitoneally or intramuscularly. The combination of bupivacaine plus pethidine showed better postoperative analgesia. Although some of the results seem promising, intraperitoneal administration of opioids cannot be recommended at this stage. An interesting study performed by Rorarius et al. [75] also assessed 30 patients undergoing tubal ligation in an inter- and intraindividual controlled manner. The verum group received 5 mg of sufentanil (2-mL solution) directly infiltrated in the cut ends of the fallopian tubes and adjacent mesosalpinx in one side; the other side was infiltrated with saline. The placebo group received saline infiltrated in both sides. There was significant pain relief on the side of the sufentanil infiltration for up to 24 hours postoperatively. Attempts in preventive pain management in laparoscopic gynecologic surgery by intraperitoneal administration of morphine failed. Keita et al. [76] injected 3 mg of morphine alone or in combination with bupivacaine 0.5% (100 mg) intraperitoneally, but could not see significant differences with regard to postoperative pain scores or analgesic requirements 24 hours postoperatively. Intravesical application of morphine showed unclear evidence in the management of bladder pain after ureteroneocystostomy in pediatric patients [77]. Continuous infusion (0.04 mL/kg/h) of 0.05, 0.375, and 0.5 mg/mL of morphine until the third postoperative day showed dosedependent reduction in pain scores for the first two postoperative days. This seems to be a peripheral opioid effect because plasma morphine concentrations were not detectable. Similar results were seen by Bertschy et al. [78], who examined 25 children between the ages of 5 months and 12 years. However, these are open studies without inclusion of a control group. El-Ghoneimi et al. [79] performed a double-blind, placebo-controlled study in 80 pediatric patients undergoing Cohen cross trigonal reimplantation. The continuous intravesical infusion of 0.04 mg/kg/h of morphine versus saline 0.08 mL/kg/h did not result in a significant reduction in pain scores during the first two postoperative days. However, all of the patients simultaneously obtained 15 mg/kg acetaminophen, which resulted in very low pain intensity scores in the control group. Thus, the sensitivity of detecting differences in pain scores possibly was insufficient. The measured plasma morphine concentrations were low, suggesting limited or no central analgesic effects. Overall, evidence for intravesical morphine analgesia remains controversial.

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Systemic application of peripherally restricted opioids Peripheral opioid analgesia induced by systemic application of peripherally restricted opioids is receiving increasing interest. For example, a recent review of the relevance of peripherally selective κ opioid-receptor agonists in visceral pain models gives a promising outlook into the future [80]. In an earlier clinical trial, patients undergoing arthroscopic knee surgery, who were treated with two oral doses of the peripherally restricted κ-agonist asimadoline 10 mg, did not show an analgesic effect [81]. This negative result may have been caused by an ineffective dose or possible hyperalgesic effects through activation of N-methyl-D-aspartate receptors. More recently, a pilot study reported that the κ opioid-receptor agonist (ADL 10-0101) was effective in treating patients with chronic pancreatitis [82••]. ADL 10-0101 is a κ-agonist with peripheral selectivity. Pain scores were reduced significantly in the six treated patients compared with those who received placebo, suggesting that peripherally restricted κ opioidreceptor agonists produce potent analgesia in patients with chronic visceral pain. Moreover, the analgesic effect was not associated with the occurrence of central side effects similar to brain-penetrating κ-agonists, suggesting a peripheral restriction of the compound. Despite these preliminary and encouraging results, more definitive clinical proof of concept for the therapeutic relevance of peripherally restricted opioids is necessary.

Conclusions Clinical evidence for peripheral opioid analgesia is demonstrated mainly in inflammatory pain states. The lack of the well-known central side effects of systemically administered opioids is an enormous advantage of this modus of pain management. Up until now, peripherally applied opioids have not shown any local side effects. Following joint surgery, the intra-articular administration of 3 to 5 mg of morphine is of considerable clinical benefit. At the end of surgery, intra-articular opioids contribute to significant pain relief in the immediate postoperative period and also may have long-term benefits. Peripheral opioids are particularly efficacious for chronic arthritic pain because they show an anti-inflammatory effect in addition to their analgesic effect. However, they still need to be compared with standard therapy. Preliminary evidence suggests that repeated local opioid treatment is less likely to develop tolerance (ie, a loss in the analgesic efficacy). Opioid treatment as an adjunct to local anesthesia for dental surgery has been shown to prolong postoperative pain relief. Topical applications of opioids may be very promising (eg, mucositis-associated pain). In post-thoracotomy and visceral pain, data for peripheral opioid analgesia are still controversial and cannot be recommended at this stage. Novel peripherally restricted opioids that do not cross the blood-brain barrier have been developed and experimental studies seem very promising. Results

of the first preclinical trials show that this new group of compounds eventually may be an alternative in the future.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

Kieffer BL, Gaveriaux-Ruff C: Exploring the opioid system by gene knockout. Prog Neurobiol 2002, 66:285–306. 2.• Sawynok J: Topical and peripherally acting analgesics. Pharmacol Rev 2003, 55:1–20. An excellent review on the increasing number of topical agents with the potential to elicit peripheral analgesia. 3. Heberden W: Commentaries on the History and Cure of Disease. New York: Hafner; 1962. 4. Wood A: New method of treating neuralgia by the direct application of opiates to the painful points. Edinburgh Med Surg J 1885, 82:265–281. 5. Tammisto T, Tammisto CH: Injection of morphine loco dolenti recommended as early as 1876. Acta Anaesthesiol Scand 2000, 44:520–523. 6. Stein C, Comisel K, Haimerl E, et al.: Analgesic effect of intraarticular morphine after arthroscopic knee surgery. N Engl J Med 1991, 325:1123–1126. 7. Stein C, Hassan AH, Lehrberger K, et al.: Local analgesic effect of endogenous opioid peptides. Lancet 1993, 342:321–324. 8. Stein C: The control of pain in peripheral tissue by opioids. N Engl J Med 1995, 332:1685–1690. 9.•• Stein C, Schäfer M, Machelska H: Attacking pain at its source: new perspectives on opioids. Nat Med 2003, 9:1003–1008. A very comprehensive and clearly written summary of experimental findings in the field of peripheral opioid analgesia. 10. Mousa SA, Machelska H, Schafer M, Stein C: Immunohistochemical localization of endomorphin-1 and endomorphin-2 in immune cells and spinal cord in a model of inflammatory pain. J Neuroimmunol 2002, 126:5–15. 11. Cabot PJ: Immune-derived opioids and peripheral antinociception. Clin Exp Pharmacol Physiol 2001, 28:230–232. 12. Machelska H, Cabot PJ, Mousa SA, et al.: Pain control in inflammation governed by selectins. Nat Med 1998, 4:1425–1428. 13. Schäfer M: Peripheral opioid analgesia: from experimental to clinical studies. Curr Opin Anaesthesiol 1999, 12:603–607. 14. Picard PR, Tramèr MR, McQuay HJ, Moore RA: Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomized controlled trials. Pain 1997, 72:309–318. 15. Kalso E, Tramèr MR, Carroll D, et al.: Pain relief from intraarticular morphine after knee surgery: a qualitative systematic review. Pain 1997, 71:127–134. 16. Gupta A, Bodin L, Holmström B, Berggren L: A systematic review of the peripheral analgesic effects of intraarticular morphine. Anesth Analg 2001, 93:761–770. 17. Murphy DB, McCartney CJ, Chan VW: Novel analgesic adjuncts for brachial plexus block: a systematic review. Anesth Analg 2000, 90:1122–1128. 18.•• Kalso E, Smith L, McQuay HJ, Moore RA: No pain, no gain: clinical excellence and scientific rigor: lessons learned from IA morphine. Pain 2002, 98:269–275. This meta-analysis critically assesses clinical trials in intra-articular morphine analgesia in arthroscopic procedures of the knee joint. 19. Marchal JM, Delgado-Martinez AD, Poncela M, et al.: Does the type of arthroscopic surgery modify the analgesic effect of intra-articular morphine and bupivacaine? A preliminary study. Clin J Pain 2003, 19:240–246. 20. Akinci SB, Saricaoglu F, Atay A, et al.: Analgesic effect of intraarticular tramadol compared to morphine after arthroscopic knee surgery. Can J Anesth 2003, 50:423–424.

Peripheral Opioid Analgesia: Clinical Applications • Oeltjenbruns and Schäfer

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Likar R, Mousa SA, Philippitsch G, et al.: Increased numbers of opioid expressing inflammatory cells do not affect intraarticular morphine analgesia. Br J Anaesth 2004, 93:375–380. 22.• Likar R, Kapral S, Steinkellner H, et al.: Dose-dependency of intraarticular morphine analgesia. Br J Anaesth 1999, 83:241–244. This article demonstrates that intra-articular morphine shows a lack of development of tolerance in a clinical setting. 23. Rosseland LA, Stubhaug H, Skoglund A, Breivik H: Intraarticular morphine for pain relief after knee arthroscopy. Acta Anaesthesiol Scand 1999, 43:252–257. 24. Rosseland LA, Stubhaug A, Grevbo F, et al.: Effective pain relief from intra-articular saline with or without morphine 2 mg in patients with moderate-to-severe pain after knee arthroscopy: a randomized, double-blind, controlled clinical study. Acta Anaesthesiol Scand 2003, 47:732–738. 25. Reuben SS, Sklar J, El-Mansouri M: The preemptive analgesic effect of intra-articular bupivacaine and morphine after ambulatory arthroscopic knee surgery. Anesth Analg 2001, 92:923–926. 26. Ossipov MH, Harris S, Lloyd P, Messineo E: An isobolographic analysis of the antinociceptive effect of systemically and intrathecally administered combinations of clonidine and opiates. J Pharmacol Exp Ther 1990, 225:1107–1116. 27. Joshi W, Reuben SS, Kilaru PR, et al.: Postoperative analgesia for outpatient arthroscopic knee surgery with intra-articular clonidine and/or morphine. Anesth Analg 2000, 90:1102–1106. 28. Buerkle H, Huge V, Wolfgart M, et al.: Intra-articular clonidine analgesia after knee arthroscopy. Eur J Anaesthesiol 2000, 17:295–299. 29. Rasmussen S, Larsen AS, Thomsen ST, Kehlet H: Intra-articular glucocorticoid, bupivacaine and morphine reduces pain, inflammatory response, and convalescence after arthroscopic meniscectomy. Pain 1998, 78:131–134. 30.• Rasmussen S, Lorentzen JS, Larsen AS, et al.: Combined intraarticular glucocorticoid, bupivacaine, and morphine reduces pain and convalescence after diagnostic knee arthroscopy. Acta Orthop Scand 2002, 73:175–178. This study reported intra-articular morphine for postoperative pain management in arthroscopic meniscectomy also enhanced the return to work. 31. Kligman M, Bruskin A, Sckliamser J, et al.: Intra-synovial, compared to intra-articular morphine provides better pain relief following knee arthroscopy meniscectomy. Can J Anesth 2002, 49:380–383. 32. Likar R, Schäfer M, Paulak F, et al.: Intra-articular morphine analgesia in chronic pain patients with osteoarthritis. Anesth Analg 1997, 84:1313–1317. 33. Stein A, Yassouridis A, Szopko C, et al.: Intra-articular morphine versus dexamethasone in chronic arthritis. Pain 1999, 83:525–532. 34. Jaureguito JW, Wilcox JF, Thisted RA, et al.: The effects of morphine on human articular cartilage of the knee: an in vitro study. Arthroscopy 2002, 18:631–636. 35. Tetzlaff JE, Brems J, Dilger J: Intra-articular morphine and bupivacaine reduces postoperative pain after rotator cuff repair. Reg Anesth Pain Med 2000, 25:611–615. 36. Henn P, Fischer M, Steuer K, Fischer A: Wirksamkeit von periartikulär appliziertem Morphin nach Schulterarthroskopien. Anaesthesist 2000, 49:721–724. 37. Scoggin JF, Mayfield G, Awaya DJ, et al.: Subacromial and intraarticular morphine versus bupivacaine after shoulder arthroscopy. Arthroscopy 2002, 18:464–468. 38. Muittari P, Kirvelä O: The safety and efficacy of intrabursal oxycodone and bupivacaine in analgesia after shoulder surgery. Reg Anesth Pain Med 1998, 23:474–478. 39. Furst I, Kryshtalskyi B, Weinberg S: The use of intra-articular opioids and bupivacaine for analgesia following temporomandibular joint arthroscopy: a prospective, randomized trial. J Oral Maxillofac Surg 2001, 59:979–983. 40. Likar R, Sittl R, Gragger K, et al.: Peripheral morphine analgesia in dental surgery. Pain 1998, 76:145–150.

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41.• Likar R, Koppert W, Blatnig H, et al.: Efficacy of peripheral morphine analgesia in inflamed, non-inflamed and perineural tissue of dental surgery patients. J Pain Symptom Manage 2001, 21:330–337. Clinical trial showing that inflammation is the prerequisite for sufficient peripheral opioid analgesia. 42. Dionne RA, Lepinski AM, Gordon SM, et al.: Analgesic effects of peripherally administered opioids in clinical models of acute and chronic inflammation. Clin Pharmacol Ther 2001, 70:66–73. 43. Likar R, Schäfer M, Trampitsch E, et al.: Topische applikation von lokalanästhetika und opioiden nach elektiver zahnextraktion. Schmerz 2004 [Epub ahead of print]. 44. Moiniche S, Mikkelsen S, Wetterslev J, Dahl JB: A qualitative systematic review of incisional local anaesthesia for postoperative pain relief after abdominal operations. Br J Anaesth 1998, 81:377–383. 45. Rosenstock C, Rasmussen H, Andersen G, Lund C: Incisional morphine has no analgesic effect on postoperative pain following inguinal herniotomy. Reg Anesth Pain Med 1998, 23:57–63. 46. Tverskoy M, Braslavsky A, Mazor A, et al.: The peripheral effect of fentanyl on postoperative pain. Anesth Analg 1998, 87:1121–1124. 47. Johansson A, Kornfält J, Nordin L, et al.: Wound infiltration with ropivacaine and fentanyl: effects on postoperative pain and PONV after breast surgery. J Clin Anesth 2003, 15:113–118. 48. Takano Y, Takano M, Kuno Y, et al.: Lidocaine or fentanyl applied to the surgical wound during spinal surgery produces potent postoperative analgesia. Can J Anesth 2003, 50:751–752. 49. Wishaw K, Billington D, O´Brien D, Davies P: The use of orbital morphine for postoperative analgesia in pterygium surgery. Anaesth Intensive Care 2000, 28:43–45. 50.•• Reuben SS, Vieira P, Faruqi S, et al.: Local administration of morphine for analgesia after iliac bone graft harvest. Anesthesiology 2001, 95:390–394. An interesting clinical trial showing that local opioid treatment may have a long-term benefit in patients, preventing the development of chronic pain states. 51. Houghton AK, Valdez JG, Westlund KN: Peripheral morphine administration blocks the development of hyperalgesia and allodynia after bone damage in the rat. Anesthesiology 1998, 89:190–201. 52. Menéndez L, Lastra A, Hidalgo A, et al.: Peripheral opioids act as analgesics in bone cancer pain in mice. Neuroreport 2003, 14:867–869. 53. Bigliardi PL, Bigliardi-Qi M, Büchner S, Rufli T: Expression of muopiate receptor in human epidermis and keratinocytes. J Invest Dermatol 1998, 111:297–301. 54. Bigliardi PL, Sumanovski LT, Büchner S, et al.: Different expression of mu-opiate receptor in chronic and acute wounds and the effect of ␤-endorphine on transforming growth factor ␤ type ii receptor and cytokeratin 16 expression. J Invest Dermatol 2003, 120:145–152. 55. Flock P: Pilot study to determine the effectiveness of diamorphine gel to control pressure ulcer pain. J Pain Symptom Manage 2003, 25:547–554. 56. Zeppetella G, Paul J, Ribero DC: Analgesic effect of morphine applied topically to painful ulcers. J Pain Symptom Manage 2003, 25:555–558. 57. Twillman RK, Long TD, Cathers TA, Mueller DW: Treatment of painful skin ulcers with topical opioids. J Pain Symptom Manage 1999, 17:288–292. 58. Ribeiro MD, Joel SP, Zeppetella G: The bioavailability of morphine applied topically to cutaneous ulcers. J Pain Symptom Manage 2004, 27:434–439. 59. Watterson G, Howard R, Goldman A: Peripheral opioids in inflammatory pain. Arch Dis Child 2004, 89:679–681.

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Peyman GA, Rahimy MH, Fernandes ML: Effects of morphine on corneal sensitivity and epithelial wound healing: implications for topical ophthalmic analgesia. Br J Ophthalmol 1994, 78:138–141. 61.•• Stiles J, Honda CN, Krohne SG, Kazacos EA: Effect of topical administration of 1% morphine sulfate solution on signs of pain and corneal wound healing in dogs. Am J Vet Res 2003, 64:813–818. Shows the effects of topical morphine during corneal wound healing. 62. Wenk HN, Nannenga MN, Honda CN: Effect of morphine sulfate eye drops on hyperalgesia in the rat cornea. Pain 2003, 105:455–465. 63. Cerchietti LC, Navigante AH, Bonomi MR, et al.: Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma. Cancer 2002, 95:2230–2236. 64.•• Cerchietti LC, Navigante AH, Körte MW, et al.: Potential utility of the peripheral analgesic properties of morphine in stomatitisrelated pain: a pilot study. Pain 2003, 105:265–273. Topical opioid treatment reduces pain intensity, duration of pain, and functional impairment in stomatitis-related pain. 65. Moiniche S, Dahl JB, Kehlet H: Peripheral antinociceptive effects of morphine after burn injury. Acta Anaesthesiol Scand 1993, 37:710–712. 66. Lilleso J, Hammer NA, Pedersen JL, Kehlet H: Effect of peripheral morphine in a human model of acute inflammatory pain. Br J Anaesth 2000, 85:228–232. 67. Long TD, Cathers TA, Twillman R, et al.: Morphine-infused silver sulfadiazine (miss) cream for burn analgesia: a pilot study. J Burn Care Rehabil 2001, 22:118–123. 68. Welte M, Haimerl E, Groh J, et al.: Effect of interpleural morphine on postoperative pain and pulmonary function after thoracotomy. Br J Anaesth 1992, 69:637–639. 69. Aykac B, Erolcay H, Dikmen Y, et al.: Comparison of intrapleural versus intravenous morphine for post-thoracotomy pain management. J Cardiothorac Vasc Anesth 1995, 9:538–540. 70. Schulte-Steinberg H, Weninger E, Jokisch D, et al.: Intraperitoneal versus interpleural morphine or bupivacaine for pain after laparoscopic cholecystectomy. Anesthesiology 1995, 82:634–640.

71.

Hernández-Palazón J, Tortosa JA, Nuno de la Rosa V, et al.: Intraperitoneal application of bupivacaine plus morphine for pain relief after laparoscopic cholecystectomy. Eur J Anaesthesiol 2003, 20:891–896. 72. Kalman SH, Jensen AG, Nyström PO, Eintrei C: Intravenous versus intraperitoneal morphine before surgery to provide postoperative pain relief. Acta Anaesthesiol Scand 1997, 41:1047–1053. 73. O’Hanlon DM, Colbert S, Ragheb J, et al.: Intraperitoneal pethidine versus intramuscular pethidine for the relief of pain after laparoscopic cholecystectomy: randomized trial. World J Surg 2002, 26:1432–1436. 74. Colbert ST, Moran K, O’Hanlon DM, et al.: An assessment of the value of intraperitoneal meperidine for analgesia postlaparoscopic tubal ligation. Anesth Analg 2000, 91:667–670. 75. Rorarius M, Suominen P, Baer G, et al.: Peripherally administered sufentanil inhibits pain perception after postpartum tubal ligation. Pain 1999, 79:83–88. 76. Keita H, Benifla JL, Le Bouar V, et al.: Prophylactic ip injection of bupivacaine and/or morphine does not improve postoperative analgesia after laparoscopic gynecologic surgery. Can J Anesth 2003, 50:362–367. 77. Duckett JW, Cangiano T, Cubina M, et al.: Intravesical morphine analgesia after bladder surgery. J Urol 1997, 157:1407–1409. 78. Bertschy C, Aubert D, Lassauge F, et al.: Intravesical morphine analgesia in pediatric urology. Prog Urol 1999, 9:474–478. 79. El-Ghoneimi A, Deffarges C, Hankard R, et al.: Intravesical morphine analgesia is not effective after bladder surgery in children: results of a randomized, double-blind study. J Urol 2002, 168:694–697. 80. Rivière PJ: Peripheral kappa-opioid agonists for visceral pain. Br J Pharmacol 2004, 141:1331–1334. 81. Machelska H, Pfluger M, Weber W, et al.: Peripheral effects of the kappa-opioid agonist EMD 61753 on pain and inflammation in rats and humans. J Pharmacol Exp Ther 1999, 290:354–361. 82.•• Eisenach JC, Carpenter R, Curry R: Analgesia from a peripherally active k-opioid receptor agonist in patients with chronic pancreatitis. Pain 2003, 101:89–95. An interesting pilot study reporting sufficient peripheral opioid analgesia induced by systemic application of a peripherally restricted opioid.