BACKGROUND:: Peripherally selective opioids may be beneficial in visceral pain management due to absence of centrally mediated side effects. The objectives of this study were:(1) to assess the effects of a peripherally selective tetrapeptide kappa-opioid receptor agonist, CR665, on experimental pain from multi-modal stimulation of skin, muscle, and viscera, and (2) contrast these effects with those of oxycodone (centrally acting opioid). METHODS:: The study was designed as a single-center, single-dose, randomized, double-blind, placebo and active-controlled, double-dummy, three-way, crossover study in healthy males. Subjects received the following treatments in randomized order:(1) CR665 (0.36 mg/kg) administered intravenously over 1 h,(2) oxycodone (15 mg) administered orally, and (3) placebo administered intravenously and orally. The following pain tests were used:(1) cutaneous pinch pain tolerance threshold,(2) pressure pain detection and tolerance thresholds,(3) cuff pressure pain tolerance threshold, and (4) pain rating thresholds to distension and thermal stimulation of the esophagus. Measurements were performed before dosing and at 30, 60, and 90 min after dosing. RESULTS:: Compared to placebo, oxycodone elevated cutaneous pinch pain tolerance (P < 0.001) and cuff pressure pain tolerance threshold (P < 0.001), as well as pain rating thresholds (visual analogue scale = 7) to esophageal distension (P < 0.001) and thermal stimulation (P < 0.002). Compared to placebo, CR665 significantly increased the pain rating threshold to esophageal distension (P < 0.005) but reduced the pain tolerance threshold to skin pinching (P = 0.007). CONCLUSION:: CR665 had a selective effect on visceral pain. Oxycodone exhibited a generalized effect, elevating thresholds for cutaneous, deep somatic, and visceral pain stimulation.

The value of opioid pharmacotherapy in the management of chronic pancreatitis pain is described. The role of kappa receptor opioid agonists and specifically oxycodone as compared to other opioid agonists is discussed. Limitations in the published studies on this topic are delineated as are difficulties in extrapolating form animal studies to clinical care. doi:10.1300/J354v21n03_11.

OBJECTIVES:: Comprehensive experimental methods are of major relevance assessing pain mechanisms in patients with chronic pain. Chronic pancreatitis is thought to involve the sensory response in other visceral organs and somatic tissue. We, therefore, aimed at exploring the pain mechanisms in chronic pancreatitis (CP) using a multimodal and multitissue stimulation approach. METHODS:: Ten patients (mean age, 50 years) with CP and 13 healthy controls (mean age, 35 years) participated. None of the patients took analgesics regularly. All were exposed to multimodal (mechanical, thermal, and electrical) experimental pain in the skin, muscles, and esophagus. RESULTS:: The patients were hyposensitive to mechanical stimulations of the skin (P = 0.001), but there were no differences in the pain to thermal and electrical stimulations. In the muscle and esophagus, no differences in pain thresholds were found. The difference between single and repeated stimulations reflecting the degree of central sensitization was 17% in controls and 36% in patients (P = 0.001). The referred pain area to electrical stimulation was 30.1 cm in the patients and 7.7 cm for the controls (P = 0.02). CONCLUSIONS:: The findings suggest that the balance among central hyperexcitability, neuroplastic changes, and descending pain-modulating pathways may explain the pain response to experimental multimodal stimulations in CP. This will likely also reflect the clinical pain mechanisms and may have important impact in selection of treatment, where drugs with potential effects on these mechanisms should be used.

Human experimental pain models require standardized stimulation and quantitative assessment of the evoked responses. This approach can be applied to healthy volunteers and pain patients before and after pharmacological interventions. Standardized stimuli of different modalities (ie, mechanical, chemical, thermal or electrical) can be applied to the skin, muscles and viscera for a differentiated and comprehensive assessment of various pain pathways and mechanisms. Using a multi-modal, multi-tissue approach, new and existing analgesic drugs can be profiled by their modulation of specific biomarkers. It has been shown that biomarkers, for example, those related to the central integration of repetitive nociceptive stimuli, can predict efficacy of a given drug in neuropathic pain conditions. Human experimental pain models can bridge animal and clinical pain research, and act as translational research providing new possibilities for designing successful clinical trials. Proof-of-concept studies provide cheap, fast and reliable information on dose-efficacy relationships and how pain sensed in the skin, muscles and viscera are inhibited.

OBJECTIVES: To gain more information of the pain mechanisms in chronic pancreatitis we applied standardized experimental pain stimulation of the duodenum, oesophagus and the skin in 12 healthy controls and 13 patients with chronic pancreatitis and typical pain attacks. METHODS: Using endoscopy a guide wire was positioned into the horizontal part of the duodenum, and a probe with a distal balloon was introduced over the guide wire. Mechanical stimuli were given as tonic (38 ml/min) or phasic (increasing volume steps of 5 ml delivered for 60 s) distensions of the balloon. After stimulation of the duodenum, the distal oesophagus was stimulated with the same protocol. Finally, the skin was stimulated with 'single and repeated burst' electrical stimuli reflecting activation of peripheral and central pain mechanisms. RESULTS: The stimuli reliably evoked both painful and non-painful local and referred sensations. The patients had hyposensitivity to both tonic and phasic mechanical stimuli of the duodenum and the oesophagus (P=0.001). Hypoalgesia was also observed to single and repeated electrical skin stimuli in the patients, most evident for repeated stimuli (P=0.001). The evoked referred pain did not differ between the groups, but the patients used on average more words from the McGill Pain Questionnaire to describe the pain evoked in the duodenum (P=0.02). CONCLUSIONS: Generalized hypoalgesia to experimental visceral and somatic stimulations was found in chronic pancreatitis. The findings suggest that the activation and modulation of central mechanisms is fundamental in pancreatic pain, and future studies should address the effect of analgesics with central effects in the treatment of these patients.

The oesophagus, stomach, duodenum and sigmoid colon were electrically stimulated in 12 healthy volunteers with a thin nasal endoscope. The painful cortical evoked potentials (EPs) were recorded from 64 surface electrodes. The early EPs with latencies < 200 ms were studied and the corresponding dipole sources were calculated. The electrical current intensities needed to evoke pain were highest in the stomach and duodenum, compared to the other segments (F = 7.8; P < 0.001; post hoc analysis P < 0.05). The EP latencies after stimulation of the stomach and sigmoid colon were shorter compared with those to stimulation of the oesophagus and duodenum (all P values < 0.001). The EP amplitudes were higher to oesophagus stimulation (all P values < 0.001 except for the early positivity). The potential fields obtained after stimulation of the most distal segments (duodenum and sigmoid colon) were in general distributed more posteriorly compared to those recorded in the more proximal regions. The EP topographies to stimulation of all gut tracts were explained by a bilateral source in the second somatosensory (SII) area, by a dipole in the anterior cingulate cortex (ACC), and by a bilateral generator in the insular cortex. However, the position of the sources significantly changed depending on the stimulated gut tract. Moreover, while the SII and ACC sources were initially activated to oesophagus and stomach stimulation, the ACC and insular activities were the earliest ones after stimulation of the lower gut segments. The findings reflect differences in pathways and brain processing of visceral nociceptive inputs coming from either upper or lower gut and may improve our understanding of the brain-gut axis in health and disease.

BACKGROUND:: The pain, urgency, and incontinence in ulcerative colitis may be related to changes in viscoelastic properties of the gut wall or to alterations of the sensory pathways. In the present study, we used an advanced rectal probe to study the mechanosensory and smooth muscle properties in patients with active disease. METHODS:: Nine patients with ulcerative colitis (mean age 39.5 years) with exacerbation limited to the rectum and sigmoid colon and 17 age-matched healthy subjects were included. The rectum was distended before and after pharmacological relaxation of the smooth muscle until moderate pain was reported, and the cross-sectional area, volume, pressure, tension, and strain were computed. To investigate central integration of a tonic stimulus, the bag was finally distended to the pain threshold; then, the cross-sectional area was held constant for 2 min. RESULTS:: The patients were hypersensitive to mechanical stimuli as assessed by the cross-sectional area (F = 21.7; P < 0.001). There were no differences in compliance or stiffness between the 2 groups, but the hypersensitivity was abolished after muscle relaxation. Together with the muscle analysis, this finding demonstrated that the smooth muscles were tonically contracted in the inflamed rectum, resulting in a decreased rectal circumference. The tonic distensions did not evoke central integration of the pain response, indicating that hyperalgesia is more likely related to peripheral factors. CONCLUSIONS:: Patients with active ulcerative colitis have hypersensitivity and increased tone of the smooth muscles, which may explain the symptoms. Drugs that affect smooth muscle contraction may be helpful in difficult cases.

Little is known about the sensory characteristics and underlying mechanisms behind secondary hyperalgesia (HA)(2 degrees HA). The aim of the present study was to investigate the relationships between two different noxious stimuli, mechanical and cold on capsaicin-induced 2 degrees HA. Fourteen healthy volunteers were exposed to three different cold stimuli (20, 10, 0 degrees C) 30 s each, on both forearms. The cold stimuli were applied before (baseline) and 8 min after intradermal administration of 50-mug capsaicin to the forearm, distally to the injection site in the inspected area of 2 degrees HA. Pain intensities were assessed immediately after each cold stimulus by means of a visual analogue scale (cold-VAS). Additionally, areas of mechanical HA (cm(2)) were assessed distally and proximally to the injection site at three different time points: 5, 8 (right after the second series of cold stimuli), and 30 min after the injection. No significant differences in cold-VAS were found between pre- and post-capsaicin injection at the tested forearm (P= 0.334), whereas significant reduction from pre- to post-injection was found in cold-VAS in the control forearm (P= 0.024). Further, 8 min after the injection, the cold stimulation led to an expansion of 2 degrees HA area (from 5.1+/-1.38 to 11.4+/-1.72 cm(2)) to punctuate stimuli distally but not proximally to the injection site (P<0.05). It is concluded that there is no HA to cold stimuli within the area of mechanical 2 degrees HA. However, cooling acts as a conditioning stimulus and expands the area of capsaicin-induced punctuate HA.

Cooling the skin induces sympathetically driven vasoconstriction, with some vasoparalytic dilatation at the lowest temperatures. Neurogenic inflammation, on the other hand, entails vasodilatation. In this study we investigated the balance between vasoconstriction and vasodilatation in an area of experimentally induced secondary hyperalgesia (2 degrees HA), in response to low-temperature stimulations. Fourteen healthy volunteers were exposed to three 30-s long cold stimuli (20, 10, and 0 degrees C) applied, at three adjacent sites, before (baseline) and 8 min after intradermal injection of 50 microg capsaicin to the volar forearm. The cold stimuli were applied distally to the injection site within the 2 degrees HA. Blood flux (BF) and skin temperatures were measured at four different regions (proximally, and distally to the capsaicin injection and at the 0, 10, and 20 degrees C thermode sites) all within the 2 degrees HA. The vascular measurements were conducted five times. Results showed a marked increase in BF after baseline cold stimulation (P<0.001) at the 0 degrees C compared with the three other sites. In addition, vasodilatory effect (elevated BF) was found following the capsaicin injection compared with baseline for all regions (P<0.001): the non-cooled area was dilated by 450+/-5.1%; The vasoconstrictive effect for the 10 and 20 degrees C did not overcome the capsaicin vasodilatation, but did reduce it, with dilatation of 364+/-7.0% and 329+/-7.3%, respectively. For 0 degrees C, a dilatation of 407+/-6.5% was seen. It is concluded that in this experimental model, and potentially in the equivalent clinical syndromes, vasodilatation induced by the inflammation is only slightly reduced by cold stimulation such that it is still dominant, despite some cold-induced vasoconstriction.

OBJECTIVE: To investigate the changes in surface and intramuscular electromyographic (EMG) activity at latent trigger points (TrPs) in the extensor carpi radialis brevis muscle after injection of either glutamate or isotonic saline into latent TrPs in the infraspinatus muscle. METHOD: Nociceptive muscle stimulation was obtained by a bolus injection of glutamate (0.2 mL, 0.5 M) into a latent TrP located in the right infraspinatus muscle in 12 healthy volunteers. A bolus of isotonic saline (0.9%, 0.2 mL) injection served as control. Injections were guided by intramuscular EMG showing resting spontaneous electrical activity at the latent myofascial TrP in the infraspinatus muscle. Intramuscular (at the TrP) and surface EMG activities of both infraspinatus and extensor carpi radialis brevis muscles were recorded before, during, and after injection for a period of 6 minutes to monitor changes produced in EMG activity. RESULTS: Glutamate injection into latent TrPs induced higher pain intensity than isotonic saline injection (P<0.001). The analysis of variance showed a significant increase in root mean square score of intramuscular EMG activity at TrP in the extensor carpi radialis brevis after glutamate (mean+/-SD: 212.0+/-215.6 muV) but not isotonic saline (mean+/-SD: 74.2+/-72.2 muV) injections (P<0.001). No changes in surface EMG activity were found. No significant changes in root mean square of intramuscular and surface EMG activity in the infraspinatus muscle were found. CONCLUSIONS: Our results show that an increased nociceptive activity at latent TrPs in the infraspinatus muscle may increase motor activity and sensitivity of a TrP in distant muscles at a same segmental level.

Importance of the field: Despite proven analgesic efficacy, opioid use is associated with frequently dose-limiting bowel dysfunction that seriously impacts patients' quality of life (QoL). Agents used at present to manage opioid-induced constipation do not address the underlying opioid receptor-mediated cause of bowel dysfunction and are often ineffective. There is, therefore, a significant need for more effective treatment options. The combination of the strong opioid oxycodone and the opioid antagonist naloxone has the potential to prevent opioid-induced bowel dysfunction (OIBD) while maintaining analgesic efficacy. Objective: To review the safety and efficacy of oral prolonged-release (PR) oxycodone/naloxone in the treatment of patients experiencing chronic pain. Areas covered in this review: A MEDLINE search was done (January 2002 - July 2009) for available literature for prolonged release oxycodone and naloxone in different patient groups. Results were limited to English-language and clinical trials. Data were also obtained from congress materials. What knowledge the reader will gain: Unmet needs of opioid pain treatment in terms of OIBD, reduced QoL and low treatment compliance, leading to reduced efficacy. A data overview demonstrates the efficacy and tolerability of PR oxycodone/naloxone in the management of severe chronic pain without the burden of severe gastrointestinal adverse events. The combined formulation of a highly effective opioid and an antagonist that acts locally to reduce gastrointestinal side effects is expected to simplify pain management. Take home message: The combination of PR oxycodone/naloxone offers the potential of maintaining normal bowel function in patients requiring opioid therapy - it is a strong analgesic that is well tolerated.

Morphine, oxycodone, and fentanyl are clinically prescribed drugs for the management of severe pain. We investigated whether these opioids possess different efficacy profiles on several types of pain in mouse pain models. When the three opioids were tested in the femur bone cancer model, all of them significantly reversed guarding behavior, whereas the effects on limb-use abnormality and allodynia-like behavior differed among the opioids. Particularly, although oxycodone (5 - 20 mg/kg) and fentanyl (0.2 mg/kg) significantly reversed limb-use abnormality, not even a high dose of morphine (50 mg/kg) could reverse it. When the effects of these opioids were examined in a sciatic nerve ligation (SNL) model of neuropathic pain, oxycodone was the most effective, producing an antinociceptive effect without affecting the withdrawal threshold of sham-treated animals. When the effects of these opioids were examined with the tail-flick test using naive animals, oxycodone, morphine, and fentanyl exhibited antinociceptive effects on thermal nociception. These results show that the three opioids exhibit different efficacy outcomes in multiple pain models and that the efficacy profile of oxycodone does not overlap those of morphine and fentanyl.

Abstract BACKGROUND: Opioid prescribing is controversial with evidence of both significant under-utilisation and over-utilisation. There is some evidence to support efficacy for chronic non-malignant pain, but community and individual harms are increasingly reported. AIMS: To review availability of opioid preparations and prescription patterns of opioids through the subsidised Pharmaceutical Benefits Scheme in Australia from 1992-2007. METHODS: Interrogation of the HIC database from 1992-2007. Item numbers for all available opioid preparations were identified, and frequency of dispensing was collected and collated. RESULTS: The number of opioids on the PBS increased from 11 preparations of 4 medications to 70 preparations of 8 medications during this period. The total number of PBS opioid prescriptions increased from 2,397,006 in 1992 to 6,998,556 in 2007. We identified a dramatic and continuing increase in prescription of oxycodone in all dose ranges. Fentanyl prescribing is increasing to a lesser degree. Morphine and tramadol prescribing appears to have plateaued. CONCLUSION: Opioid use is increasing. There is a pressing need for co-ordinated assessment of efficacy and harms to facilitate quality usage of opioids.

PURPOSE OF REVIEW: Since the introduction of oral immediate release and controlled-release oxycodone preparations to the market in the 1990s, the clinical use and scientific interest in oxycodone has increased greatly. RECENT FINDINGS: Recent studies have shown that the pharmacokinetics of oxycodone are dependent on age of the patient and therefore individual titration of the dose is necessary, especially in the elderly. Oxycodone has good oral bioavailability and it produces more predictable plasma concentrations than morphine, which has a poor and more variable bioavailability. Oxycodone has clinically significant drug interactions with drugs affecting cytochrome P450 3A enzymes. Clinical studies have demonstrated that oxycodone is a useful opioid analgesic in acute postoperative pain, cancer pain, visceral pain and chronic nonmalignant pain. SUMMARY: The availability of oxycodone preparations has increased its clinical use exponentially during the last decade. Further clinical studies are still needed to fully understand its clinical pharmacology. Oxycodone is still a new 'old' drug whose pharmacology and clinical potential is not yet fully understood.

In the present study, we demonstrated that repeated treatment with fentanyl, but not morphine or oxycodone, causes a rapid desensitization to its ability to block the hyperalgesia associated with the attenuation of mu-opioid receptor resensitization in mice in a chronic pain-like state. In contrast, no such effect was noted in beta-endorphin knockout mice under the chronic pain-like conditions. On the assumption that beta-endorphin might be released within the spinal cord under pain-like conditions, we further examined whether beta-endorphin could be responsible for a desensitization and resensitization of fentanyl under the chronic pain. In cultured cells, unlike morphine, fentanyl and oxycodone induced a robust mu-opioid receptor internalization and, in turn, its resensitization. In the presence of beta-endorphin, the internalized mu-opioid receptor induced by fentanyl, but not oxycodone, remained within the cytosolic component even after washing out. The findings suggest that beta-endorphin could attenuate the resensitization of mu-opioid receptors. This phenomenon may explain the high degree of tolerance to fentanyl that develops with hyperalgesia caused by a chronic pain-like state.

As it is well known opioids are the most powerful drugs used for acute and chronic pain, although, their several serious side effects, such as respiratory depression, mental clouding, constipation, and tolerance dependence producing capacity, as well as large interpatient variability in responses limit their safe everyday use. Furthermore, the treatment of certain types of pain (e.g. neuropathic pain) is not very satisfactorily managed. Consequently, there is a continuous need to find analgesics efficient against chronic neuropathic pain and avoid these side actions and still retain opioid like potency. There are several possible way to find new targets for these purposes. Recently opioid receptors have been identified on peripheral processes of sensory neurons. These findings provide new insights into intrinsic mechanisms of pain control and suggest innovative strategies for developing drugs and alternative approaches to pain treatment. In the effort to discover better analgesic drugs for chronic pain, attention is being paid to specific ion channels at the periphery, include members of transient receptor potential family (TRPV1, capsaicin receptors), as well as P2x receptors, sensitive to purines released from tissue injury. A special tetradotoxin-resistant, voltage dependent type of sodium channel is associated with dorsal root ganglia neurons is blocked by mexiletine, used in chronic pain. A synthetic peptide analogue of marine snail toxin ziconitine blocks N-type calcium channels. GABA and NMDA receptors are also involved in the antinociceptive actions of gabapentin and ketamine, respectively. Furthermore nicotine and analogues (epibatidine) induce analgesia through nicotinic ACh receptors. We studied mostly the peripheral targets of hydrophilic heterocyclic opioids in antinociceptive processes.

The oral "around-the clock" administration of sustained-release strong opioids has been recommended for the long-term treatment of patients suffering from chronic severe pain. At present a plethora of products are available in Germany. Modern galenics even allow for only once-daily oral application without clinically relevant negative chronobiological interference. This application scheme has been shown to improve compliance and sleep quality, factors that influence treatment outcome. Randomized controlled studies revealed no relevant differences between the different strong opioids with respect to efficacy and tolerability. However, hydromorphone and oxycodone appear to be advantageous over morphine due to a lack of immunosuppression. Hydromorphone has the additional benefit of a lower risk of intoxication by accumulation of active metabolites in patients with decreased renal function. As a result, although morphine has been regarded as the standard for the treatment of chronic severe pain, hydromorphone and oxycodone may be better and safer alternatives for certain patient groups (e.g. older age, multimorbidity, cancer).