naloxone and Burns

The purpose of this case series was to review the management of burn patients who requested ultrarapid opioid detoxification under anesthesia after extended duration of narcotic use for chronic pain related to burn injury.. The treatment plan of six opioid-dependent burn patients was analyzed to assess the effectiveness of our detoxification practice to date. Demographic and clinical information was used to characterize the patient population served: age, burn size, injury severity, duration of narcotic use before detoxification intervention, and length of hospitalization stay. Daily narcotic consumption, in morphine equivalent units, was noted both before and after detoxification.. Six burn patients (average age, 31 years) underwent detoxification at the Burn Center during a hospitalization lasting between 1 day and 2 days. Average burn size was 38% total body surface area (range, 17-65); average Injury Severity Score was 30 (range, 25-38). Mean duration of narcotic use was 672 days (range, 239-1,156 days); average use of narcotics at time of detoxification was >200 units daily. Mean outpatient consumption for opioids after the intervention was minimal (<25 units/d). No complications were noted during any procedures.. The results of ultrarapid opioid detoxification under anesthesia suggests that it is safe and effective for treating opioid addiction in military burn casualties when a coordinated, multidisciplinary approach is used. Safety and effectiveness to date validate current practice and supports incorporation into clinical practice guidelines. Further clinical research is warranted to identify those patients who may benefit most from detoxification and to determine the timing of such treatment.

Topics: Adult; Analgesics, Opioid; Burns; Humans; Male; Military Personnel; Naloxone; Narcotic Antagonists; Pain; Substance Withdrawal Syndrome; United States

Mu-opioid-receptor antagonists have been extensively studied in experimental research as pharmacological tools uncovering mechanisms of pain modulation by the endogenous opioid system. In rodents, administration of high doses of mu-opioid-receptor antagonists after the resolution of an inflammatory injury has demonstrated reinstatement of nociceptive hypersensitivity indicating unmasking of latent sensitization. In a recent human study, pain hypersensitivity assessed as secondary hyperalgesia area (SHA), was reinstated 7 days after a mild thermal injury, in 4 out of 12 subjects after a naloxone infusion.The aims of the present study are first, to replicate our previous findings in a larger-sized study; second, to examine if high sensitizers (subjects presenting with large SHA after a thermal injury) develop a higher degree of hypersensitivity after naloxone challenge than low sensitizers (subjects presenting with restricted SHA after a thermal injury); and third to examine a dose-response relationship between 3 stable naloxone concentrations controlled by target-controlled infusion, and the unmasking of latent sensitization.Healthy participants (n = 80) underwent a screening day (day 0) with induction of a thermal skin injury (47°C, 420 seconds, 12.5 cm). Assessment of SHA was performed 1 and 2 hours after the injury. Using an enriched design, only participants belonging to the upper quartile of SHA (Q4, high sensitizers; n = 20) and the lower quartile of SHA (Q1, low sensitizers; n = 20) continued the study, comprising 4 consecutive days-days 1 to 4. Thermal skin injuries were repeated on day 1 and day 3, whereas day 2 and day 4 (7 days after day 1 and day 3, respectively) were target-controlled infusion days in which the subjects were randomly allocated to receive either naloxone (3.25 mg/kg, 4 mg/mL) or placebo (normal saline) intravenous. The primary outcome was SHA assessed by weighted-pin instrument (128 mN) 0, 1, 2, and 165 to 169 hours after the thermal injury (day 1-4). The secondary outcomes were pin-prick pain thresholds assessed by weighted-pin instrument (8-512 mN) at primary and secondary hyperalgesia areas (days 1-4).The naloxone-induced unmasking of latent sensitization is an interesting model for exploring the transition from acute to chronic pain. The results from the present study may provide valuable information regarding future research in persistent postsurgical pain states.

Topics: Adult; Burns; Cross-Over Studies; Denmark; Double-Blind Method; Humans; Hyperalgesia; Infusions, Intravenous; Male; Naloxone; Narcotic Antagonists; Pain; Pain Management; Pain Measurement; Pain Threshold

Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain, have demonstrated reinstatement of tactile hypersensitivity following administration of μ-opioid-receptor-antagonists. In the present study in humans, we analyzed the effect of naloxone when given after the resolution of secondary hyperalgesia following a first-degree burn injury.. Twenty-two healthy volunteers were included in this placebo-controlled, randomized, double-blind, cross-over study. Following baseline assessment of thermal and mechanical thresholds, a first-degree burn injury (BI; 47°C, 7 minutes, thermode area 12.5 cm(2)) was induced on the lower leg. Secondary hyperalgesia areas around the BI-area, and separately produced by brief thermal sensitization on the contralateral thigh (BTS; 45°C, 3 minutes, area 12.5 cm(2)), were assessed using a polyamide monofilament at pre-BI and 1, 2, and 3 hours post-BI. At 72 hrs, BI and BTS secondary hyperalgesia areas were assessed prior to start of a 30 minutes intravenous infusion of naloxone (total dose 21 microg/kg) or placebo. Fifteen minutes after start of the infusion, BI and BTS secondary hyperalgesia areas were reassessed, along with mechanical and thermal thresholds.. Secondary hyperalgesia areas were demonstrable in all volunteers 1-3 hrs post-BI, but were not demonstrable at 72 hrs post-burn in 73-86% of the subjects. Neither magnitude of secondary hyperalgesia areas nor the mechanical and thermal thresholds were associated with naloxone-treated compared to placebo-treated subjects.. Naloxone (21 microg/kg) did not reinstate secondary hyperalgesia when administered 72 hours after a first-degree burn injury and did not increase BTS-generated hyperalgesia. The negative results may be due to the low dose of naloxone or insufficient tissue injury to generate latent sensitization.

Topics: Adult; Animals; Burns; Cross-Over Studies; Double-Blind Method; Female; Humans; Hyperalgesia; Male; Naloxone; Narcotic Antagonists; Pain Threshold; Placebos

Opioid antagonists may change the responses in models of experimental hyperalgesia. This indicates a possible involvement of the endogenous opioid system in these models. The aim of the present study was to evaluate whether activation of the endogenous opioid system could be demonstrated in the human burn injury model of cutaneous hyperalgesia, using an intravenous challenge with the non-selective opioid antagonist naloxone.. We studied 25 healthy male volunteers aged 20-31 yrs in a randomised, double-blind, triple crossover design. A 25x50 mm rectangular burn injury was produced on the calf on 3 separate days, at least 1 week apart. Subjects received an intravenous bolus dose of naloxone 0.4 mg, 10 mg or placebo 3 h after induction of the burn injury.. Primary and secondary hyperalgesia was induced by the burn injury. Naloxone did not affect any of the measured variables: heat pain detection threshold in non-injured or injured tissue, pain produced by short or prolonged noxious heat in non-injured or injured tissue, secondary hyperalgesia elicited by pin prick or stroke, or pain produced by short or prolonged noxious mechanical stimulation in non-injured tissue. No significant adverse effects of naloxone were encountered.. Activation of an endogenous opioid response following induction of hyperalgesia in human volunteers by a burn injury could not be demonstrated with an intravenous naloxone challenge. These findings suggest that the endogenous opioid response is not a confounding factor in this model.

Topics: Adult; Burns; Hot Temperature; Humans; Hyperalgesia; Male; Naloxone; Opioid Peptides

Several studies have demonstrated the presence of opioid inducible receptors on peripheral nerves and peripheral antinociceptive effects of opioids. However, the effects of peripheral opioid administration in man are controversial. Our study used a randomized, double-blind, placebo-controlled, three-way crossover design in a human model of acute inflammatory pain (heat injury). We studied 18 healthy volunteers who each received morphine locally (2 mg), morphine systemically (2 mg), or placebo on three separate study days. The subjects received morphine infiltration subcutaneously (s.c.). 1 h before heat injury (47 degrees C, 7 min) and naloxone infiltration s.c. (0.2 mg) 2.5 h after the heat injury. Hyperalgesia to mechanical and heat stimuli were examined using von Frey hairs and thermodes, and pain was rated using a visual analogue scale. The burns produced significant hyperalgesia, but local morphine infiltration neither reduced pain during the burn, nor primary or secondary hyperalgesia to mechanical and heat stimuli after the burn. In conclusion, peripherally applied morphine had no acute antinociceptive effects in this human model of acute inflammatory pain.

Topics: Administration, Cutaneous; Adult; Analgesics, Opioid; Burns; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphine; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Pain Measurement

This study aimed to investigate the effect of opium dependency on the healing of third-degree burns in rats.. Twenty-four rats were randomly divided to experimental and control groups. In the experimental group, opium was added to the drinking water for 21 days at increasing concentrations. The control group did not receive opium. To prove dependency on opium in the rats, naloxone was injected intraperitoneally. Full-thickness burn wounds were inflicted by applying an iron cuboid preheated to 94°C to the flank of all rats for 20 s. On day 14 after burn injury, full-thickness biopsies were taken. Blind histopathologic evaluation was performed to assess length and thickness of the re-epithelialization area, number of neutrophils, fibroblasts, mononuclear cells and new vessels, and percentage of tissue in repair (neutrophilic exudate, and granulation and fibrous tissue). Findings were analyzed using SPSS software.. The wound surface area was 95 ± 43.35 mm(2) in the control group and 120.4 ± 50.12 mm(2) in the experimental group (p = 0.224). The findings show that opium dependency has no significant effect on the healing of burn wounds in rats except for the number of monocytes on day 14 (p < 0.05).. Morphine dependency does not seem to be as effective on third-degree burn healing.

Topics: Animals; Burns; Disease Models, Animal; Female; Fibroblasts; Leukocytes, Mononuclear; Naloxone; Narcotic Antagonists; Neutrophils; Opioid-Related Disorders; Rats; Rats, Sprague-Dawley; Wound Healing

The heat pain threshold was assessed in 32 healthy participants after a mild burn on the dorsal surface of each hand, after injection of an opioid antagonist (80 microg naloxone) or vehicle alone (0.2 mL saline) into the burnt skin of 1 hand, and after repeated painful immersion of this hand in cold water for up to 180 seconds. We hypothesized that sensitivity to heat would decrease at the burn-injured site after the immersions, due to local release of opioids into the burnt skin. Naloxone augmented cold-induced pain during the immersions in participants who tolerated the longest immersions, implying that release of endogenous opioids suppressed cold-pain. After the immersions, sensitivity to heat decreased at the burn-injured site in the immersed hand, but naloxone did not block this effect. Instead, naloxone altered sensitivity to heat in unburnt skin, implying that thermal hyperalgesia at sites of burn injury masked the modulatory effects of opioids. In particular, naloxone blocked a decrease in sensitivity to heat at an unburnt site on the contralateral hand of participants who tolerated the longest immersions, consistent with central or systemic opioid release. Naloxone reduced sensitivity to heat at unburnt sites in participants who tolerated medium-length immersions, suggesting that an increase in systemic or central opioid activity evoked thermal hyperalgesia in this group. In addition, in a small group of participants who tolerated only brief immersions, naloxone blocked decreases in sensitivity to heat at an unburnt site in the immersed hand. These findings suggest that repeated painful immersions trigger local opioid release in participants who tolerate only brief immersions, and elicit central or systemic opioid release in participants who tolerate longer immersions.. This article demonstrates that repeated immersion of the hand in painfully cold water increases opioid activity and that the increase in opioid activity exerts multiple opposing effects on sensitivity to heat. Individual differences in the response to opioids might contribute to individual differences in pain tolerance.

Topics: Adolescent; Adult; Burns; Female; Humans; Hyperalgesia; Injections, Subcutaneous; Male; Naloxone; Narcotic Antagonists; Nociceptors; Opioid Peptides; Pain; Pain Threshold; Sensory Receptor Cells; Skin Temperature

The aim of this study was to investigate local opioid effects in the inflamed skin of healthy human volunteers. To induce inflammation, the circular tip of a 10-mm-diameter probe was heated to 48 degrees C and applied for 120 seconds to a site on each forearm of 24 healthy participants. Thirty minutes later, 0.2 mL of normal saline was injected subcutaneously into 1 inflamed site, and the opioid antagonist naloxone hydrochloride (80 microg in 0.2 mL) was injected subcutaneously into the other inflamed site. Participants completed tests of pain sensitivity (heat pain thresholds, heat pain ratings, and mechanical pain ratings) before and after the injections. Fentanyl citrate (10 microg in 0.2 mL) was then injected into the pretreated sites, and pain sensitivity was measured again. The thermal injuries produced thermal and mechanical hyperalgesia that did not differ between the saline and naloxone sites. After the fentanyl injections, decreases in thermal and mechanical hyperalgesia were greater at the saline site than the naloxone site. These findings demonstrate that pretreatment with naloxone blocks local opioid effects produced by the subcutaneous injection of a low dose of fentanyl in the inflamed skin of healthy humans. Thus, peripheral opioid receptors could be a therapeutic target for painful cutaneous disorders.. This article demonstrates that activation of opioid receptors in the skin inhibits sensitivity to painful mechanical and thermal stimuli. Thus, local application of low-dose opioid medications could relieve painful skin disorders.

Topics: Adolescent; Adult; Analgesics, Opioid; Burns; Dose-Response Relationship, Drug; Female; Fentanyl; Humans; Hyperalgesia; Male; Naloxone; Narcotic Antagonists; Nociceptors; Pain Measurement; Pain Threshold; Receptors, Opioid; Sensory Receptor Cells; Skin

This paper studied the effect of post-burn local hyperthermia on burn induced injury.. A second-degree burn injury was induced on the right and left flanks of Balb/c mice. Thirty-two burn wounds were divided into four groups. Opioid receptor blocking was done for groups 3 and 4 by intra-peritoneal administration of Naloxone (NLX) 30 min before the thermal injury. Local hyperthermia (45 degrees C, 30 s) was applied only for the burn wounds of groups 2 and 4. Twenty-four hours after burn injury, the burned wounds were assessed for the level of iNOS (by immunohistochemistry) and the number of hair follicles (as an indicator of tissue injury).. The wounds that received hyperthermia (group 2) had significantly more hair follicles (p < 0.001) compared to the control wounds (group 1). There was no significant difference between the number of hair follicles and acute inflammation of group 1 and group 3 (NLX + burn). Group 4 (NLX + burn + hyperthermia) had significantly fewer hair follicles compared to group 1 (p < 0.001), group 2 (p < 0.001) and group 3 (p < 0.001). The level of iNOS in groups 1, 3 and 4 was not significantly different but significantly more than group 2 (p < 0.001, p < 0.001 and p < 0.001, respectively).. The results showed that local hyperthermia after second degree burn decreased the tissue injury and iNOS expression. It is also concluded that endogenous opioid response may have a key role in the above mentioned effects of post-burn local hyperthermia.

Topics: Animals; Burns; Hair Follicle; Hyperthermia, Induced; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Necrosis; Nitric Oxide Synthase Type II; Wound Healing

Local thermal injury to the paw leads to an increased sensitivity to a noxious stimulus applied to the site (primary thermal hyperalgesia) and an increased sensitivity to tactile stimuli in skin sites adjacent to the primary injury (secondary tactile allodynia; 2 degrees TA). We sought to define the peripheral and spinal actions of mu opioids in regulating 2 degrees TA. First, a mild thermal injury was induced on one heel, producing 2 degrees TA. This 2 degrees TA was blocked by pretreatment, but not posttreatment, with a topical mu-opioid agonist, loperamide (1.7%-5%). Second, 2 degrees TA was blocked by intrathecal morphine (0.1-10 microg) pre- and postinjury. 2 degrees TA reappeared when systemic naloxone was given before, but not after, injury in intrathecal morphine-pretreated rats. Intrathecal remifentanil, a short-lasting mu-opioid agonist, infused periinjury (3 microg/min), did not block subsequent primary thermal hyperalgesia, but it produced a dose-dependent (0.3-3 microg/min) abolition of 2 degrees TA. Local tissue injury leads to 2 degrees TA by the activation of opiate-sensitive afferents and the initiation of a cascade that persists in the absence of that initiating injury-induced stimulus.. Sensitivity to touch observed in areas adjacent to injury is blocked by opioids applied before, but not after, injury. This suggests that injury-activated opioid-sensitive fibers are responsible for sensitization and reveals a cascade that is diminished by pretreatment but not posttreatment, providing a rationale for adequate analgesia before injury (surgery) has occurred.

Topics: Administration, Topical; Analgesics, Opioid; Animals; Burns; Hindlimb; Hyperalgesia; Injections, Spinal; Loperamide; Male; Morphine; Naloxone; Narcotic Antagonists; Neural Pathways; Neurons, Afferent; Pain Threshold; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Remifentanil; Spinal Cord; Touch

Preclinical and clinical evidence indicates that locally administered opioid agonists produce an antihyperalgesic effect through peripheral opioid receptors in inflamed tissue. Loperamide, a mu opioid agonist, does not cross the blood-brain barrier and therefore lacks central effects after systemic administration. The authors defined the effects of topical loperamide on a thermal injury-induced hyperalgesia.. In halothane-anesthetized rats, thermal injury was induced by placing the plantar surface of a hindpaw on a hot plate (52.0+/-1 degrees C) for 45 s. Loperamide was prepared in a cream emulsion (ADL 2-1294B, 0.5%, 1.7%, and 5.0%). The drug was applied as follows: before or after injury on the injured paw and on a normal paw and after injury on the injured paw of morphine-tolerant rats. Paw withdrawal latency to a radiant heat source was measured to determine the nociceptive threshold. A pharmacokinetic study was performed with the use of 14C-labeled drug.. Thermal injury yielded a significant thermal hyperalgesia. Loperamide, but not the vehicle, posttreatment on the injured paw resulted in a dose-dependent antihyperalgesic effect, which was reversible with naloxone (1 mg/kg given intraperitoneally). Treatment with loperamide on the normal paw produced short-lasting hypoalgesia, but the effect was not reversible with naloxone. Pretreatment at 1 and 2 but not 4 h with loperamide was effective. A rightward shift of the dose-response curve was observed in rats made tolerant to systemic morphine with subcutaneous morphine pellets. No rats with drug treatment displayed any evident behavior changes (eg., loss of corneal or pinna reflexes or change in ambulation). Drug activity in the tissue revealed an elimination half life of 2.3 h and negligible concentration in the blood.. Loperamide, a peripherally acting mu opioid agonist, applied topically at the site of inflammation possesses a significant antihyperalgesic action without any systemic side effects.

Topics: Analgesics; Analgesics, Opioid; Animals; Burns; Drug Tolerance; Hindlimb; Hyperalgesia; Loperamide; Male; Morphine; Naloxone; Narcotic Antagonists; Nociceptors; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu

The present study was performed to explore the effects of intrathecal administration of calcitonin gene-related peptide8-37 (CGRP(8-37)) on the hindpaw withdrawal latency (HWL) to pressure in rats with one thermally injured hindpaw. Furthermore, the interaction of CGRP(8-37)and naloxone was studied. Thermal injury was performed by dipping the left paw into 60 degrees C for 20 s. This induced a significant increase in the volume of the left hindpaw (P<0.001) and significant bilateral decreases of the latency of hindpaw withdrawal response to mechanical stimulation (Left: P<0.001; right: P<0.05). Intrathecal administration of 10, 20 and 40 nmol of CGRP(8-37), but not of 1 or 5 nmol, induced a significant bilateral increase in HWLs (P<0.001). The effect of CGRP(8-37) was partly reversed by intrathecal injection of naloxone at a dose of 32 and 64 microg respectively. Using radioimmunoassay, we found a significant bilateral increase in the concentration of CGRP-like immunoreactivity in the perfusate of both hindpaws 24 h after unilateral thermal injury (left: P< 0.001; right: P< 0.05). There was also an increase in the amount of CGRP-like immunoreactivity in the cerebrospinal fluid (P< 0.001), but not in plasma. The results indicate that CGRP plays a role in the transmission of nociceptive information in the spinal cord of thermally injured rats. Furthermore, our findings suggest that opioids can modulate CGRP-related effects in the spinal cord.

Topics: Animals; Antibody Specificity; Burns; Calcitonin Gene-Related Peptide; Edema; Extracellular Space; Hot Temperature; Inflammation; Injections, Spinal; Male; Miotics; Naloxone; Narcotic Antagonists; Nociceptors; Pain; Peptide Fragments; Physical Stimulation; Pressure; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Reaction Time; Reflex; Spinal Cord

Thermal injury to the skin increases transfer of plasma fluids and proteins into the interstitium. Here, protein extravasation and edema were produced by immersion of the anesthetized rat's paw in 48 degrees C or 58 degrees C water for 5 min. Protein extravasation was measured by Evans blue dye leakage into the skin and edema by increases in skin weights. Corticotropin-releasing factor (CRF), having the human/rat 41-amino acid sequence, was efficacious in reducing these indices of thermal injury. Injected i.v. at microgram doses or intradermally at nanogram doses, it inhibited the protein extravasation and edema produced by heat. The intradermal median inhibitory dose (ED50) of CRF against protein extravasation elicited by 48 degrees C water was 21.8 times lower than the i.v. ED50, indicating that CRF's actions occurred locally in the paw skin. Ovine-CRF and dynorphin A(1-13) injected i.v. inhibited the protein extravasation and edema induced by 58 degrees C water, but morphine, ethylketocyclazocine and FK 33,824 (a stabilized enkephalin analog) were not active at this temperature. CRF may be a powerful inhibitor of the acute inflammatory response of the skin to thermal irritation.

Topics: Animals; Blood Proteins; Burns; Capillary Permeability; Corticotropin-Releasing Hormone; Dose-Response Relationship, Drug; Edema; Male; Naloxone; Rats