Nausea and vomiting side effects with opioid analgesics during treatment of chronic pain: mechanisms, implications, and management options

A B S T R A C T Objectives. Gastrointestinal (GI) side effects such as nausea and vomiting are common following opioid analgesia and represent a significant cause of patient discomfort and treatment dissatisfaction. This review examines the mechanisms that produce these side effects, their impact on treatment outcomes in chronic pain patients, and counteractive strategies. Results. A number of mechanisms by which opioids produce nausea and vomiting have been identified. These involve both central and peripheral sites including the vomiting center, chemoreceptor trigger zones, cerebral cortex, and the vestibular apparatus of the brain, as well as the GI tract itself. Nausea and vomiting have a negative impact on treatment efficacy and successful patient management because they limit the effective analgesic dosage that can be achieved and are frequently reported as the reason for discontinuation of opioid pain medication or missed doses. While various strategies such as antiemetic agents or opioid switching can be employed to control these side effects, neither option is ideal because they are not always effective and incur additional costs and inconvenience. Opioid-sparing analgesic agents may provide a further alternative to avoid nausea and vomiting due to their reduced reliance on mu-opioid signalling pathways to induce analgesia. Conclusions. Nausea and vomiting side effects limit the analgesic efficiency of current opioid therapies. There is a clear need for the development of improved opioid-based analgesics that mitigate these intolerable effects

Differential Modulation by [D-Pen2 , D-Pen5]Enkephalin and Dynorphin A-(1 -1 7) of the Inhibitory Bladder Motility Effects of Selected Mu Agonists in Vivo1

ABSTRACT The possibility that the delta agonist, [D-Pen2, D-Pen5]enkephali

Intrathecal bombesin-induced inhibition of gastrointestinal transit: requirement for an intact pituitary-adrenal axis

The role of the pituitary-adrenal axis in the inhibition of gastrointestinal transit caused by intrathecal administration of bombesin was examined. Bombesin (0.3-10 [mu]g) slowed transit by this route in a dose-related manner. Either hypophysectomy or adrenalectomy prevented the inhibition of gastrointestinal transit associated with bombesin (10 [mu]g, i.th.). The inhibitory gut effects of this peptide were not prevented in sham-operated rats. Intrathecal bombesin-induced inhibition of gastrointestinal transit is thus dependent upon an intact pituitary-adrenal axis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26176/1/0000255.pd

An efficient intrathecal delivery of small interfering RNA to the spinal cord and peripheral neurons

We have developed a highly effective method for in vivo gene silencing in the spinal cord and dorsal root ganglia (DRG) by a cationic lipid facilitated delivery of synthetic, small interfering RNA (siRNA). A siRNA to the delta opioid receptor (DOR), or a mismatch RNA, was mixed with the transfection reagent, i-Fect™ (vehicle), and delivered as repeated daily bolus doses (0.5 μg to 4 μg) via implanted intrathecal catheter to the lumbar spinal cord of rats. Twenty-four hours after the last injection, rats were tested for antinociception by the DOR selective agonist, [D-Ala(2), Glu(4)]deltorphin II (DELT), or the mu opioid receptor (MOR) selective agonist, [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO). Pretreatment with the siRNA, but not the mismatch RNA or vehicle alone, blocked DELT antinociception dose-dependently. The latter was concomitant with a reduction in the spinal immunoreactivity and receptor density of DOR, and in DOR transcripts in the lumbar DRG and spinal dorsal horn. Neither siRNA nor mismatch RNA pretreatment altered spinal immunoreactivity of MOR or antinociception by spinal DAMGO, and had no effect on the baseline thermal nociceptive threshold. The inhibition of function and expression of DOR by siRNA was reversed by 72 hr after the last RNA injection. The uptake of fluorescence-tagged siRNA was detected in both DRG and spinal cord. The low effective dose of siRNA/i-Fect™ complex reflects an efficient delivery of the siRNA to peripheral and spinal neurons, produced no behavioral signs of toxicity. This delivery method may be optimized for other gene targets

Intrathecal morphine slows gastrointestinal transit in rats

Intrathecal (i.th.) (by direct lumbar puncture) and intraperitoneal (i.p.) administration of morphine (30-100 [mu]g/rat) caused a dose-related inhibition of gastrointestinal transit in the rat. Pretreatment with i.th. naloxone (5 [mu]g at -5 min) reversed the effects of i.th., but not i.p., morphine. These results suggest that the spinal cord appears to be a target site for the inhibitory effects of morphine on gastrointestinal transit in the rat.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25467/1/0000005.pd

Estimation of the affinity of naloxone at supraspinal and spinal opioid receptors in vivo: Studies with receptor selective agonists

The apparent affinity of naloxone at cerebral and spinal sites was estimated using selective mu [D-Ala2, Gly-ol5]-enkephalin (DAGO) and delta [D-Pen2, D-Pen5]enkephalin] (DPDPE) opioid agonists in the mouse warm water tail-withdrawal test in vivo; the mu agonist morphine was employed as a reference compound. The approach was to determine the naloxone pA2 using a time-dependent method with both agonist and antagonist given intracerebroventricularly (i.c.v.) or intrathecally (i.th.); naloxone was always given 5 min before the agonist. Complete time-response curves were determined for each agonist at each site in the absence, and in the presence, of a single, fixed i.c.v. or i.th. dose of naloxone. From these i.c.v. or i.th. pairs of time-response curves, pairs of dose-response lines were constructed at various times; these lines showed decreasing displacement with time, indicative of the disappearance of naloxone. The graph of log (dose ratio - 1) vs. time was linear with negative slope, in agreement with the time-dependent form of the equation for competitive antagonism. From this plot, the apparent pA2 and naloxone half-life was calculated at each site and against each agonist. The affinity of naloxone was not significantly different when compared between agonists after i.c.v. administration. A small difference was seen between the affinity of i.th. naloxone against DPDPE and DAGO; the i.th. naloxone pA2 against morphine, however, was not different than that for DPDPE and DAGO. The naloxone half-life varied between 6.6 and 16.9 min, values close to those previously reported for this compound. These results suggest that the agonists studied may produce their i.c.v. analgesic effects at the same receptor type or that alternatively, the naloxone pA2 may be fortuitously similar for mu and delta receptors in vivo. Additionally, while the affinity of naloxone appears different for the receptors activated by i.th. DAGO and DPDPE, further work may be necessary before firm conclusions regarding the nature of the spinal analgesic receptor(s) can be drawn.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25982/1/0000048.pd

Characterization of Antiallodynic Actions of ALE-0540, a Novel Nerve Growth Factor Receptor Antagonist, in the Rat1

There is growing evidence that nerve growth factor (NGF) may function as a mediator of persistent pain states. We have identified a novel nonpeptidic molecule, ALE-0540, that inhibits the binding of NGF to tyrosine kinase (Trk) A or both p75 and TrkA (IC50 5.88 6 1.87 mM, 3.72 6 1.3 mM, respectively), as well as signal transduction and biological responses mediated by TrkA receptors. ALE-0540 was tested in models of neuropathic pain and thermally-induced inflammatory pain, using two routes of administration, a systemic i.p. and a spinal intrathecal (i.th.) route. Morphine was also tested for comparison in the antiallodynia model using mechanical stimuli. We show that either i.p. or i.th. administration of ALE-0540 in rats produced antiallodynia in the L5/L6 ligation model of neuropathic pain. The calculated A50 values (and 95% confidence intervals) for ALE- 0540 administered i.p. and i.th. were 38 (17.5– 83) mg/kg and 34.6 (17.3– 69.4) mg, respectively. ALE-0540 given i.th., at doses of 30 and 60 mg, also blocked tactile allodynia in the thermal sensitization model. Although morphine displayed greater potency [A50 value of 7.1 (5.6–8.8) mg/kg] than ALE- 0540 in anti-allodynic effect when given i.p. to L5/L6-ligated rats, it was not active when administered i.th. These data suggest that a blockade of NGF bioactivity using a NGF receptor antagonist is capable of blocking neuropathic and inflammatory pain and further support the hypothesis that NGF is involved in signaling pathways associated with these pain states. ALE-0540 represents a nonpeptidic small molecule which can be used to examine mechanisms leading to the development of agents for the treatment of pain

Studies in vitro with ICI 174, 864, [D-Pen2, D-Pen5]-enkephalin (DPDPE) and [D-Ala2, NMePhe4, Gly-ol]-enkephalin (DAGO)

The interactions of a proposed, selective delta receptor antagonist (ICI 174, 864) and selective agonists at mu and delta receptors, [D-Ala2, NMePhe4, Gly-ol]-enkephalin (DAGO) and [D-Pen2, D-Pen5]-enkephalin (DPDPE), respectively, have been studied using the electrically-stimulated mouse isolated vas deferens (MVD) and the guinea-pig isolated ileum (GPI). Incubation of increasing concentrations of ICI 174, 864 (10, 30, 100 and 300 nM) produced a dose-related and parallel rightward displacement of the DPDPE dose-response curve in the MVD. In contrast, ICI 174, 864 (300-3000 nM) failed to affect the DAGO dose-response curve in the same tissue. Analysis of the DPDPE-ICI 174, 864 interaction in the MVD using the pA2 method revealed a Schild plot slope of -0.68 suggesting the involvement of more than one population of receptors. ICI 174, 864 (300 nM) failed to antagonize DPDPE in the GPI at doses up to 30 uM. These results suggest that (a) ICI 174, 864 acts as a selective delta antagonist in the MVD; (b) DPDPE interacts with mu receptors in the MVD but only at very high concentrations, and (c) delta receptors appear not to be of functional importance in the GPI.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25769/1/0000330.pd

Inhibition of p38-MAPK signaling pathway attenuates breast cancer induced bone pain and disease progression in a murine model of cancer-induced bone pain

<p>Abstract</p> <p>Background</p> <p>Mechanisms driving cancer-induced bone pain are poorly understood. A central factor implicated to be a key player in the process of tumorigenesis, osteoclastogenesis and nociception is p38 MAPK. We determined the role of p38 MAPK in a mouse model of breast cancer induced bone pain in which mixed osteolytic and osteoblastic remodeling occurs.</p> <p>Results</p> <p>In cancer-treated mice, acute as well as chronic inhibition of p38 MAPK with SB203580 blocked flinching and guarding behaviors in a dose-dependent manner whereas no effect on thresholds to tactile stimuli was observed. Radiographic analyses of bones demonstrated that chronic inhibition of p38 MAPK reduced bone loss and incidence of spontaneous fracture in cancer-treated mice. Histological analysis of bones collected from mice treated with the p38 MAPK inhibitor showed complete absence of osteoblastic growth in the intramedullary space as well as significantly reduced tumor burden.</p> <p>Conclusions</p> <p>Blockade of non-evoked pain behaviors but not hypersensitivity suggests differences in the underlying mechanisms of specific components of the pain syndrome and a possibility to individualize aspects of pain management. While it is not known whether the role of p38 MAPK signaling can be expanded to other cancers, the data suggest a need for understanding molecular mechanisms and cellular events that initiate and maintain cancer-induced bone pain for effective management for both ongoing pain as well as breakthrough pain.</p