Subcutaneous Administration Of Morphine Research Articles

Biotransformation of Morphinone and Its Glutathione Adduct Derived from Morphine by Anaerobic Gut Microbes in Guinea Pigs.

Morphinone (MO) and its glutathione adduct (MO-GSH) are excreted into bile of guinea pigs after subcutaneous administration of morphine (M). In the present study, we examined metabolites of M in guinea pig feces. Surprisingly, minimal amounts of MO and MO-GSH were excreted into the feces, whereas dihydromorphine (DHM) and dihydromorphinone (DHMO), which are not found in bile of guinea pigs administered M, were detected in the feces. Incubation of MO and MO-GSH with the contents of the large intestine under anaerobic conditions resulted in their conversion into DHMO. These results suggest that MO-GSH undergoes C-S cleavage by gut microbes to form MO, which is anaerobically reduced to DHMO excreted into feces.

The orexin receptors in the ventral tegmental area are involved in the development of sensitization to expression of morphine-induced preference in rats.

Recent studies have shown that orexin neurons in the lateral hypothalamus send a compelling project to the ventral tegmental area (VTA). Besides, orexin-1 (OX1) and orexin-2 (OX2) in the VTA are necessary for the development of morphine-induced place preference. Also, sensitivity to morphine can reinforce the rewarding effects of morphine. The current study aims to determine the role of VTAs orexin receptors in morphine sensitization in rats. In 84 adult male albino Wistar rats, two separate cannulae bilaterally implanted into the VTA. They received intra-VTA infusions of SB334867 (0.1, 1 and 10 nM) and TCS OX2 29 (1, 7 and 20 nM) as OX1 and OX2 receptor antagonists, respectively, 10 min before subcutaneous administration of morphine (5 mg/kg) during 3-day sensitization period. After a 5-day drug-free period, the conditioned place preference (CPP) paradigm induced by subthreshold doses of morphine (0.5 mg/kg), and CPP scores were measured by EthoVision software. The results revealed that the blockade of both OX1 and OX2 receptors within the VTA reduced the expression of morphine-induced CPP in the sensitized rats. It is plausible that VTAs orexin receptors are involved in the development/acquisition of sensitization to morphine-induced CPP in the rats.

Involvement of D1- and D2-like dopamine receptors within the rat nucleus accumbens in the maintenance of morphine rewarding properties in the rats.

Previous studies on drug abuse have shown that response to drug-associated cues exist during prolonged abstinence. In succession to previous investigations in our laboratory on morphine dependence and our research on acquisition and expression phases of morphine-conditioned place preference (CPP), in this study we attempt to determine the effects of intraaccumbal administration of SCH-23390, as a D1-like receptor antagonist, and sulpiride, as a D2-like receptor antagonist, in the maintenance of morphine-induced CPP in rats. Seventy-nine adult male Wistar rats weighing 200-280 g were bilaterally implanted with cannulas into the nucleus accumbens. During the 3-day conditioning phase, the animals received daily subcutaneous administration of morphine (5 mg/kg). CPP score and locomotor activity of animals were recorded by Ethovision software. Different doses (0.25, 1, 4 μg per 0.5 μL vehicle) of D1- and D2-like antagonists were bilateral injected daily after the expression phase and during the extinction phase. Our findings revealed that intraaccumbal administration of D1-like and D2-like antagonists after the CPP test shortened the extinction phase in the rats. The results suggested that the existence of the dopamine receptors in the nucleus accumbens was important for the maintenance of morphine-rewarding properties during the extinction phase. Therefore, dopamine receptors may be considered as a promising therapeutic agent in preventing the maintenance of morphine-rewarding effects in dependent individuals. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Lidocaine Reversible Inactivation of the Central Nucleus of Amygdala Impairs Acquisition, Consolidation, and Retrieval of Morphine State-Dependent Learning in Rat

Background/Aims: Morphine causes state-dependent learning that its mechanism and brain-related structures are not fully understood. This study aimed to determine whether lidocaine reversible inactivation of the central nucleus of the amygdala (CeA) could affect acquisition, consolidation, and retrieval of morphine state-dependent learning. Methods: One hundred twenty male Wistar rats were allocated into 15 experimental groups. Subcutaneous administration of morphine (5 mg/kg) induced morphine state-dependent learning. Intra-CeA injection of Lidocaine hydrochloride was performed 5 min before each morphine session for transient inactivation of the CeA. The step-through latency and the time spent in the dark compartment were measured using passive avoidance learning task. Results: Our results showed that pretraining, posttraining, and pretest inhibition of the CeA severely impaired acquisition, consolidation, and retrieval of morphine state-dependent learning. Conclusion: These data revealed the involvement of the CeA in different stages of memory and morphine state-dependent learning.

Ghrelin modulates morphine-nicotine interaction in avoidance memory: Involvement of CA1 nicotinic receptors

Ghrelin is a stomach-derived hormone which regulates appetite and energy balance in the body. Recent studies show that ghrelin has been linked to the learning and memory process. Ghrelin also modulates reward properties of addictive drugs. However, the involvement of ghrelin in cognitive effects of addictive drugs has not been examined yet. The goal of present study is to examine the effect of intra-CA1 administration of ghrelin on morphine response for avoidance task alone or in combination with nicotine. Here, we also investigated the role of hippocampal nicotinic cholinergic receptors in possible interaction of the drugs in adult male Wistar rats. Results showed that subcutaneous administration of morphine immediately after training impaired memory in the test day and induced amnesia, while intra-CA1 pre-injection of ghrelin prevented amnesic effect of morphine and improved memory. Also, systemic administration of nicotine five min prior to morphine administration dose-dependently inhibited morphine-induced amnesia. The results showed that intra-CA1 injection of an ineffective dose of ghrelin (0.03 nmol/µl) potentiated the nicotine (0.2 mg/kg, s.c.) response on amnesia induced by morphine. This stimulatory effect was inhibited by mechamylamine, a non-competitive nicotinic receptor antagonist. Moreover, post-training administration of drugs (ghrelin, nicotine and mecamylamine) alone had no effect on memory consolidation. In conclusion, present study suggests the significant role of ghrelin in morphine-related memory and its interactive effect with nicotine in avoidance task via CA1 nicotinic receptors.

The role of nucleus accumbens shell on acquisition and retrieval stages of morphine state dependent learning.

In the present study, the effect of transient inactivation of the shell subregion of the nucleus accumbens (NAC shell) by lidocaine on the acquisition and retrieval stages of passive avoidance learning (PAL) and memory and morphine state-dependent learning (SDL) in male wistar rats was investigated. Adult male wistar rats weighing (220-250 g) were used. Lidocaine hydrochloride was bilaterally injected into the shell area of the nucleus accumbens 5 min before of subcutaneous morphine administration. pre-training and pre-test infusion of lidocaine into the NAC shell significantly impaired PAL and memory. Furthermore, Pre-training administration of morphine (5 mg/kg, s.c.) in a step-through passive avoidance task induced state-dependent learning with impaired memory retrieval on the test day. The impairment of memory was restored after pre-test administration of the same dose of morphine. This phenomenon has been named as morphine state dependent learning (SDL). Moreover, Pre-training and pre-test inactivation of the NAC shell impaired morphine SDL. The results suggest the role of NAC shell as a common structure in the PAL and morphine SDL. It is suggested that NAC shell as a common area plays a critical role in the acquisition and retrieval stages of PAL and also morphine SDL.

Age-dependent antinociception and behavioral inhibition by morphine

In current clinical practice, morphine is dosed in older patients based on patient-weight, with different calculations for adjustment. However, at present, neither clinical experience nor the literature offers a clear evidence base for the relationship between antinociception, behavioral effects and morphine administration in older patients. In this study, we compared the nociceptive response of 8 and 24 week old rats after subcutaneous administration of morphine per body weight and analyzed their behavior using an advanced multi-conditioning system. Residual morphine in all major tissues was determined. We observed prolonged morphine-induced antinociception in older rats compared to younger rats. Moreover, morphine significantly stimulated locomotor and rearing behavior 180 min after injection, which was significantly higher in the 8 week compared to 24 week old rats. Tissue analysis from animals extracted 240 min post-injection revealed a significantly higher concentration of residual morphine in the brains of older versus younger animals when standardized on tissue weight. However, this effect was not observed when residual morphine was standardized on protein content. Collectively, our data suggest that in older rats morphine exhibits higher antinociception and increased behavioral inhibition compared to younger animals. This effect is likely due to a significantly higher accumulation of morphine in the brain of older animals.

Safety and effectiveness of coadministration of intrathecal sufentanil and morphine in hyperbaric bupivacaine-based spinal anesthesia for cesarean section

Subarachnoid block is a widely used technique for cesarean section. Opioids adding to the local anesthetics can improve its quality. In this prospective, randomized, double blind, controlled trial, we compared the effects of coadministration of intrathecal sufentanil and morphine with intrathecal sufentanil and a single administration of subcutaneous morphine. Sixty-four pregnant women scheduled for elective cesarean section under spinal anesthesia were assigned to two groups according to the way of administration of morphine: intrathecal sufentanil (5 microg) plus intrathecal morphine (150 microg) (ITM group), and intrathecal sufentanil (5 microg) plus single administration of 10 mg subcutaneous morphine (SCM group). In both groups, the local anesthetic used was hyperbaric bupivacaine 0.5 percent (10 mg). Both groups received 1 g acetaminophen every 6 hours. In the postoperative period, pain was recorded on a 0-100 visual analog scale (VAS) and intravenous tramadol (100 mg) was administered if VAS score was >40 mm. Collateral effects, such as nausea, itching, respiratory depression, and sedation were assessed. VAS scores at rest and on coughing were significantly higher in the SCM group than in the ITM group between 3 and 24 hours. The mean titrated dose of tramadol consumed was also significantly greater in the SCM group than in the ITM group (p < 0.05). The time to first administration of tramadol was lower in the SCM group versus the ITM group (p < 0.05). The incidence of nausea was significantly lower in the SCM group than in the ITM group (p < 0.05). There was no significant group difference in the incidence of pruritus (p > 0.05). In conclusion, coadministration of sufentanil and morphine into the subarachnoid space was effective and provided longer pain relief than intrathecal sufentanil plus a single injection of subcutaneous morphine, despite a higher incidence of side effects such as nausea and vomiting.

Protective effects of atorvastatin against morphine-induced tolerance and dependence in mice

BackgroundIn this study, we evaluated the effects of atorvastatin, a lipid-lowering medication on morphine-induced tolerance and dependence in mice. MethodsTolerance was induced by subcutaneous administration of morphine (20mg/kg) to animals, twice a day for 9days. Atorvastatin was given at the doses of 5, 10 and 20mg/kg, 30min before each morphine administration, once daily for 9days. Hot plate test was employed to assess antinociceptive effect of morphine on days 1, 3, 5, 7 and 9. Dependence was evaluated by naloxone-precipitated withdrawal syndrome. We attempted to verify withdrawal regulation of induced nitric oxide synthase (iNOS), astroglia marker, glial fibrillary acidic protein (GFAP), ionized calcium-binding protein (Iba1), a microglia activation marker, a pro-inflammatory mediator, tumor necrosis alpha (TNF-α) and immune receptor, toll like receptor 4 (TLR-4) genes by real-time polymerase chain reaction (RT-PCR). Lipid peroxidation was estimated by assessing malondialdehyde (MDA) content in the spinal cord of animals. ResultsTolerance to antinociceptive effects of morphine was observed on days 7 and 9. Decrease in morphine-induced antinociception was reversed by concomitant intraperitoneal administration of atorvastatin (10 and 20mg/kg). Atorvastatin (10 and 20mg/kg) mitigated naloxone-induced withdrawal parameters. Brain expression levels of TNF-α, GFAP, Iba1 and iNOS increased in morphine withdrawn animals which were attenuated by nine days treatment with atorvastatin. Increased MDA was also normalized in withdrawn animals received atorvastatin. ConclusionAtorvastatin exhibits meaningful protective effects against both tolerance to antinociceptive effects of morphine and withdrawal-induced behavioral profile. Neuroprotective effects of atorvastatin is further supported via inhibition of glia activity and antioxidant effects.

Injectable peptide hydrogels for controlled-release of opioids

Peptide-based hydrogels as a drug carrier system for the subcutaneous administration of morphine.

Differential effects of intra-accumbal orexin-1 and -2 receptor antagonists on the expression and extinction of morphine-induced conditioned place preference in rats

Orexinergic neurons originate from the hypothalamic nuclei, sending projections toward mesolimbic regions such as the nucleus accumbens (NAc). In this study, an attempt was made to determine the effects of intra-accumbal administration of SB334867 as an orexin-1 receptor (OX1R) antagonist and TCS OX2 29 as an orexin-2 receptor (OX2R) antagonist in the expression and maintenance of morphine-induced conditioned place preference (CPP) in rats. One hundred and five adult Wistar rats weighing 200–280g were bilaterally implanted with cannulae into the NAc. During the 3-day conditioning phase, animals received daily subcutaneous administration of morphine (5mg/kg). CPP score and locomotor activity of animals were recorded by Ethovision software. Different doses of bilateral injections of the OX1R and OX2R antagonists (3, 30 and 300μg/0.5μl DMSO) were administered just before the conditioning test or daily injection during extinction phase. Our finding revealed that intra-accumbal administration of OX1R not OX2R antagonist just before the CPP test attenuated the expression of the morphine-induced CPP. However, the blockade of these two kinds of receptors shortened the extinction phase in the rats. This effect was more significant in intra-NAc OX1R antagonist-treated animals. The results suggested that OX1R within the NAc may be necessary for the morphine-induced expression. Additionally, it seems that the existence of the orexin receptors in the NAc was important for the maintenance of morphine rewarding properties during the extinction phase. Therefore, orexins may be considered as a promising therapeutic agent in preventing the expression and maintenance of morphine rewarding effects on dependent individuals.

Intra-accumbal CB1 receptor blockade reduced extinction and reinstatement of morphine

The limbic dopaminergic reward system is the main target of morphine-like drugs which begins from the ventral tegmental area (VTA) and sends its dopaminergic projections to the nucleus accumbens (NAc), amygdala, hippocampus and prefrontal cortex. Cannabinoid receptors exist in afferent neurons from these areas to the NAc and can modulate glutamate synaptic transmission in the NAc. Cannabinoids can interact with the opiate system in reward-related behaviors; nevertheless these systems' interaction in extinction duration and reinstatement has not been shown. In the present study, the effects of bilateral intra-accumbal administration of AM251, a CB1 receptor antagonist, on the duration of the extinction phase and reinstatement to morphine were investigated by conditioned place preference (CPP) paradigm. Forty eight adult male albino Wistar rats were used. Bilateral intra-accumbal administration of AM251 (15, 45 and 90μM/0.5μl DMSO per side) was performed. Subcutaneous administration of morphine (5mg/kg) in three consecutive days was used to induce CPP. The results showed that administration of the maximal dose of AM251 during the extinction period significantly reduces duration of extinction and reinstatement to morphine. Administration of the middle dose during the extinction period significantly attenuated reinstatement to morphine. A single microinjection of the middle dose just before the reinstatement phase significantly attenuated reinstatement to morphine only, while bilateral intra-accumbal administration of neither the lowest dose nor the vehicle (DMSO) had any effects. These results for the first time indicated that CB1 receptors within the NAc are involved in the maintenance of morphine rewarding properties, and morphine seeking behaviors in extinguished morphine-induced CPP rats.

The influence of electrical stimulation on dorsal raphe nucleus with different current intensities on morphine-induced conditioned place preference in male rats.

The dorsal raphe nucleus (DRN) influences a wide range of behavioral and physiological processes. The purpose of the present study was to test the effects of electrical stimulation of the DRN with different current intensities on morphine-induced conditioned place preference (CPP). Male Wistar rats were divided for experimental groups (n=7). Stimulating electrodes were stereotaxically implanted into the DRN in anesthetized rats. We investigated the influences of electrical stimulation of the DRN with different current intensities with ineffective and effective dose of morphine (0.5 and 2.5mg/kg, respectively) on morphine-induced CPP. Subcutaneous administration of morphine 2.5mg/kg produced significant CPP in comparison with saline group. The stimulation of the DRN with different current intensities (10, 25, 50 and 100μA) in combination with an effective dose of morphine did not show significant differences on acquisition phases, whereas there were significant decreases on expression phases versus to the morphine group on CPP only in current intensity 100μA. The stimulation of the DRN with different current intensities in combination with an ineffective dose of morphine showed significant increases in current intensities (50 and 100μA) on acquisition phases of CPP, but did not show significant differences on expression phases versus to the morphine group on CPP. It is possible that electrical stimulation of the DRN with changes in concentration of serotonin or involving other transmitters such as glutamate and GABA would be involved with these changes of CPP.

Effects of ginsenosides on opioid-induced hyperalgesia in mice

Opioid-induced hyperalgesia (OIH) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use. OIH can limit the clinical use of opioid analgesics and complicate withdrawal from opioid addiction. In this study, we investigated the effects of Re, Rg1, and Rb1 ginsenosides, the bioactive components of ginseng, on OIH. OIH was achieved in mice after subcutaneous administration of morphine for 7 consecutive days three times per day. During withdrawal (days 8 and 9), these mice were administered Re, Rg1, or Rb1 intragastrically two times per day. On the test day (day 10), mice were subjected to the thermal sensitivity test and the acetic acid-induced writhing test. Re (300 mg/kg) inhibited OIH in both the thermal sensitivity test and the acetic acid-induced writhing test. However, the Rg1 and Rb1 ginsenosides failed to prevent OIH in either test. Furthermore, Rg1 showed a tendency to aggravate OIH in the acetic acid-induced writhing test. Our data suggested that the ginsenoside Re, but not Rg1 or Rb1, may contribute toward reversal of OIH.

Role of intra-accumbal cannabinoid CB1 receptors in the potentiation, acquisition and expression of morphine-induced conditioned place preference

Recent studies demonstrate a functional interaction between opioid and endogenous cannabinoid system. These two systems possess similar pharmacological effects on drug addiction and reward. The present study was designed to investigate the role of intra-accumbal cannabinoid CB1 receptors in the acquisition and expression of morphine-induced conditioned place preference (CPP). Two-hundred forty eight adult male albino Wistar rats were used in these experiments. Using a 3-day schedule of conditioning, it was found that subcutaneous administration of morphine (0.2–10mg/kg) induced CPP at the doses of 5 and 10mg/kg. Solely intra-accumbal administration of WIN55,212-2 (1, 2 and 4mmol/0.5μl DMSO) as CB1 receptor agonist could induce CPP. Also, our results showed that ineffective dose of WIN55,212-2 (1mmol) when administered before the ineffective dose of morphine (2mg/kg) could induce the CPP and potentiate the rewarding effect of morphine. On the other hand, intra-accumbal injection of the cannabinoid CB1 receptor antagonist AM251 (90μmol/0.5μl DMSO) alone induced a significant conditioned place aversion. Moreover, intra-NAc injection of AM251 (45 and 90μmol/0.5μl DMSO) inhibited morphine-induced CPP. Interestingly, injection of WIN55,212-2 (1, 2 and 4mmol) or AM251 (15, 45 and 90μmol) into the NAc had no effect on the expression of morphine (5mg/kg)-induced CPP. These observations provide evidence that cannabinoid CB1 receptors in the NAc are involved in development of reward-related behaviors and they can potentiate the rewarding effects of morphine. It seems that these receptors can affect the reward modulatory system at the level of nucleus accumbens in rats.

σ1Receptors Are Involved in the Visceral Pain Induced by Intracolonic Administration of Capsaicin in Mice

Visceral pain is an important and prevalent clinical condition whose treatment is challenging. Sigma-1 (σ1) receptors modulate somatic pain, but their involvement in pure visceral pain is unexplored. The authors evaluated the role of σ1 receptors in intracolonic capsaicin-induced visceral pain (pain-related behaviors and referred mechanical hyperalgesia to the abdominal wall) using wild-type (WT) (n = 12 per group) and σ1 receptor knockout (σ1-KO) (n = 10 per group) mice, selective σ1 receptor antagonists (BD-1063, S1RA, and NE-100), and control drugs (morphine and ketoprofen). The intracolonic administration of capsaicin (0.01-1%) induced concentration-dependent visceral pain-related behaviors and referred hyperalgesia in both WT and σ1-KO mice. However, the maximum number of pain-related behaviors induced by 1% capsaicin in σ1-KO mice (mean ± SEM, 22 ± 2.9) was 48% of that observed in WT animals (46 ± 4.2). Subcutaneous administration of the σ1 receptor antagonists BD-1063 (16-64 mg/kg), S1RA (32-128 mg/kg), and NE-100 (8-64 mg/kg) dose-dependently reduced the number of behavioral responses (by 53, 62, and 58%, respectively) and reversed the referred hyperalgesia to mechanical control threshold (0.53 ± 0.05 g) in WT mice. In contrast, these drugs produced no change in σ1-KO mice. Thus, the effects of these drugs are specifically mediated by σ1 receptors. Morphine produced an inhibition of capsaicin-induced visceral pain in WT and σ1-KO mice, whereas ketoprofen had no effect in either mouse type. These results suggest that σ1 receptors play a role in the mechanisms underlying capsaicin-induced visceral pain and raise novel perspectives for their potential therapeutic value.

Different current intensities electrical stimulation of prelimbic cortex of mPFC produces different effects on morphine-induced conditioned place preference in rats

The medial prefrontal cortex (mPFC) is a part of brain reward system involved in higher cognitive functions such as learning and memory. The mPFC receives strong dopaminergic innervations from ventral tegmental area (VTA) that comprises a portion of the mesolimbic dopaminergic system (MLDS), and in turn sends glutamate projection to both the VTA and nucleus accumbens (NAc). In the present study, we investigated the influence of electrical stimulation with different current intensities on prelimbic cortex (PL, subdivision of mPFC) (25, 50, 100, and 150μA) with and without an effective dose of morphine (0.5 and 5mg/kg) on CPP during conditioning and post-conditioning phases. Subcutaneous administration of morphine 5mg/kg produced significant CPP in comparison with saline group. Our findings also showed that electrical stimulation of PL (100μA) suppressed morphine-induced CPP that reveals impaired learning and memory formation in the process of conditioning through the blocking connection from the hippocampus to the prelimbic cortex of mPFC. A lowest current intensity (25μA) in combination with ineffective dose of morphine (0.5mg/kg) increased morphine-induced CPP probability via the prove reward system.

Effects of aqueous saffron extract (Crocus sativus L.) on the acquisition and reinstatement of morphine-induced conditioned place preference in mice

Objective: In the present study, the effects of aqueous saffron extract (Crocus sativus L.) on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP) in mice were investigated. Materials and Methods: Subcutaneous administration of morphine (40 mg/kg for four days) produced place preference. Intraperitoneal administration of aqueous extract (40 and 80 mg/kg for four days) 30 min before the morphine administration decreased the acquisition of morphine CPP. In other groups of animal, following extinction of a place preference induced by morphine (40 mg/kg), single administration of morphine (10 mg/kg) reinstated the place reference. The aqueous extract (80 mg/kg) 30 min before this priming dose of morphine blocked morphine-induced reinstatement of place preference. Results: These results show that aqueous saffron extract can reduce the acquisition and reinstatement of morphine-induced conditioned place preference.

Morphine sensitization in the pentylenetetrazole-induced clonic seizure threshold in mice: Role of nitric oxide and μ receptors

Behavioral sensitization occurs after repeated administration of μ-opioid receptor agonists following a drug-free period. It seems that the changes in dopaminergic systems induced by μ-opioid receptor agonists play a crucial role in behavioral sensitization to opioids. Nitric oxide also plays a role in some behavioral effects of morphine, including sensitization to the locomotor-stimulating effect. This study investigated whether morphine sensitization appears in seizure threshold and the possible role of μ-opioid receptor and nitric oxide in this sensitization. Sensitization was produced by daily injections of morphine (0.1, 0.5, 1, 5, 15, or 30 mg/kg), followed by a 10-day washout period. Then the challenge test was performed using morphine (0.1, 0.5, 1, 5, 15, or 30 mg/kg) in different groups. To assess clonic seizure threshold, pentylenetetrazole (PTZ) was administered intravenously. Subcutaneous administration of morphine (0.1 and 0.5 mg/kg) induced sensitization in PTZ-induced clonic seizures in mice. Intraperitoneal administration of L-NAME (20 mg/kg), a nonselective inhibitor of nitric oxide synthase, or naltrexone (10 mg/kg), an opioid receptor antagonist, along with morphine inhibited morphine-induced sensitization in PTZ-induced seizure threshold. In conclusion, at low doses, morphine induces sensitization in PTZ-induced clonic seizures in mice probably as a result of the interaction with μ-receptors and nitric oxide.

Spinal analgesia: where is the evidence?

Dear Editor, We read with interest the systematic review by Myers and colleagues [1]. The authors conducted a thorough review of the literature on intraspinal techniques for pain management in cancer patients. They did a good job summarizing the existing studies and consensus. However, we would like to express our concerns regarding the authors' conclusions. Specifically, they stated in the abstract that “the evidence supported the use of intraspinal techniques for cancer pain management... Intraspinal techniques monitored by an interprofessional health care team should be included as part of a comprehensive cancer pain management program”. It is unclear how the authors arrived at these conclusions. The authors identified three randomized controlled trials comparing intraspinal with systemic analgesia [2–4]. The first study by Vanino et al. found no statistically significant difference in pain [2]; the second study by Smith et al. revealed a borderline statistical significance of questionable clinical value [3], while the third council study revealed no difference in pain control between epidural and subcutaneous administration of morphine [4]. The methodologic quality of the three included studies needs to be highlighted. Two studies reported no sample size calculations, and both appeared to be under-powered [2, 4]. Two were open-label studies [2, 3] which could significantly affect how pain and side effects were assessed. Finally, all were supported by pharmaceutical companies. It is known that industry support is an important source of bias in clinical trials [5, 6]. The authors also wrote in their discussion that “the main advantages of intraspinal analgesia for cancer pain are the delivery of adequate pain control and fewer side effects than with the conventional analgesia routes. Disadvantages of intraspinal analgesia include the technically demanding insertion procedure and close patient follow-up required by skilled healthcare personnel”. The authors may also want to emphasize the procedural risk and complications related the catheter and/or pump, such as infections, bleeding, and cerebrospinal fluid leak. The limited reporting of this important information could be potentially misleading. Based on these findings, perhaps the most appropriate conclusion is that the role of intraspinal opioids for the management of cancer pain has not been established and that adequately powered, well-designed, independently funded clinical trials are required before this complex, risky, and expensive intervention becomes part of routine care.