Clinical and experimental effects of informational stress

Under certain conditions, information may become stressful. In the initial stages of our research we found that informational stress can result in fatigue, anxiety, sleeplessness, and excitability. Later we found further symptoms, such as tachycardia, palpitations, chest pain, abdominal pain, increase or decrease of appetite, diarrhoea or constipation, muscle cramps, back pain, headache, tremor, dizziness, diaphoresis, tics, and so on. Some of these symptoms might be the result of cathecholamine increased secretion, others of a decrease of endogenous opioids. Because in the initial stage of stress analgesia may occur, we studied the clinical and experimental evolution of the pain threshold and its clinical manifestations. We found that after the initial analgesia, there follows a stage of hyperalgesia; the symptoms of this stage very much resemble those of the opioid abstinence syndrome. The evolution of this syndrome is enhanced by naloxone, an opioid antagonist, and it is attenuated by clonidine and propranolol, used in the treatment of opioid abstinence syndrome. Thus we demonstrated that in the latter stage of stress, there is diminished secretion of endogenous opioids and an acute tolerance to them.     

Opioids confer myocardial tolerance to ischemia: interaction of delta opioid agonists and antagonists

BACKGROUND: Mammalian hibernation biology is now known to be mediated by delta opioids. The altered myocellular physiology of hibernation closely parallels that of hypothermic ischemia used to protect the heart for cardiac surgery. METHODS AND RESULTS: The present study examined the interaction of delta opioid agonists and antagonists on myocardial tolerance to ischemia. By means of a nonhibernating isolated rabbit heart model, functional and metabolic myocardial parameters were assessed during nonischemic baseline and postischemic recovery periods. Control hearts with standard cardioplegic protection alone were compared with those with cardioplegia plus preperfusion with a delta opioid agonist, a delta opioid antagonist, or both. All hearts were then subjected to 2 hours of global ischemia. Compared with cardioplegia alone, postischemic left ventricular developed pressure, coronary flows, and myocardial oxygen consumption were all increased with administration of delta opioid agonists and decreased below baseline with delta opioid antagonists. Functional recovery of left ventricular developed pressure was improved with opioids (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid agonist: 65 +/- 5 mm Hg, P <.01) and inhibited with antagonists (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid antagonist: 17 +/- 5 mm Hg, P <.05), and true to form, the protective opioid effect was negated when combined with an antagonist (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid agonist and delta opioid antagonist: 42 +/- 4 mm Hg, P = not significant). CONCLUSIONS: This study demonstrates that cardiac tolerance to ischemia may be mediated by delta opioids.     

Opioid tolerance and dependence: an inevitable consequence of chronic treatment?

Although opioids provide effective analgesia, largely unsubstantiated concerns about opioid-induced tolerance, physical dependence and addiction have limited their appropriate use. As a consequence, many patients receive inadequate treatment for both malignant and non-malignant pain. However, it has been shown that analgesic tolerance develops less frequently during chronic opioid administration in a clinical context than in animal experiments, and that instituting an appropriate dosing regimen can minimise withdrawal symptoms. Early studies had suggested that addiction might result from chronic opioid therapy, though more recent data indicate a low risk in patients with no history of drug abuse. New treatment regimens may also reduce the risk of tolerance, physical dependence and addiction. Long-acting preparations, such as transdermal fentanyl and possibly some forms of other slow release opioids, which maintain constant opioid concentrations in the plasma, minimise the occurrence of the 'between-dose' symptoms such as withdrawal and opioid-induced euphoria. This review discusses the development of tolerance, physical dependence and addiction during opioid therapy, and the influence of these factors on the choice of treatment.     

Useful adjuvants for postoperative pain management

Adjuvants are compounds which by themselves have undesirable side-effects or low potency but in combination with opioids allow a reduction of narcotic dosing for postoperative pain control. Adjuvants are needed for postoperative pain management due to side-effects of opioid analgesics, which hinder recovery, especially in the increasingly utilized ambulatory surgical procedures. NMDA antagonists have psychomimetic side-effects at high doses, but at moderate doses do not cause stereotypic behavior but allow reduction in opioid dose to obtain better pain control. Alpha-2 adrenergic agonists cause sedation, hypotension and bradycardia at moderate doses, but at low doses can be opioid sparing especially in spinal administration. Gabapentin-like compounds have low potency against acute pain, but in combination with opioids allow a reduction in opioid dose with improved analgesia. Corticosteroids may have only a limited role as adjuvants while acetylcholine esterase inhibitors may have too many side-effects. Newer adjuvants will be needed to reduce opioid dose and concomitant side-effects, even more as same day surgeries become more routine.     

Ultra-low dose ketamine and memantine treatment for pain in an opioid-tolerant oncology patient

Patients taking high-dose opioids chronically for tumor-related or neuropathic pain may develop pain that is refractory to opioids. One option for control of such pain is the use of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. We describe a case of opioid-refractory pain that responded to a low-dose IV infusion of ketamine in the inpatient setting. The patient was then successfully transitioned to oral memantine for long-term outpatient management, in a novel use of this oral NMDA receptor antagonist. We present recent findings from basic research on pain mechanisms to explain why opioid tolerance, as in this patient, may contribute to the analgesic benefit of NMDA receptor antagonists.     

Opioid mechanisms and opioid drugs

The opioid system comprises four receptor subtypes: μ (MOP), κ (KOP), δ (DOP) (i.e. the so called ‘classical’ opioid receptors) and the more recently identified nociceptin/orphanin FQ peptide (N/OFQ) receptor (NOP). Selective endogenous peptides, typically cleaved from larger precursor proteins, have been identified for all subtypes. Both classical and non-classical opioid receptors couple to inhibitory, pertussis toxin-sensitive G-proteins. Opioid receptors activate the same major intracellular pathways, which include: closing of voltage-sensitive calcium channels; opening of potassium channels and subsequent cellular hyperpolarization; and inhibition of cyclic AMP production through inhibition of the enzyme adenylate cyclase. All current, clinically used opioids work through activation of the MOP receptor. In an experimental setting, co-administration of MOP and DOP agonists has been shown to have a synergistic analgesic action. Administration of DOP-receptor antagonists has also been shown to reduce tolerance, physical dependence and other side effects of MOP-receptor agonists, without detriment to their analgesic action. In animal models NOP agonists are analgesic spinally and hyperalgesic supraspinally. Conversely, NOP antagonists are analgesic at supraspinal sites. NOP knockout mice show a partial loss of tolerance to morphine and up-regulation of N/OFQ production in chronic morphine-tolerant mice. Analgesic tolerance that develops from repeated exposure to morphine was markedly attenuated in NOP knockout mice. Based on these findings an alternative route for opioid development might be the development of ligands with mixed action at MOP, DOP and NOP.     

Nociceptin and the ORL1 receptor: pharmacology of a new opioid receptor

Molecular biological investigations led to the discovery of the ORL1 receptor ( opioid receptor like-1 receptor) and its endogenous ligand nociceptin. Although its sequence and structure are closely related to traditional opioid receptors, the ORL1 receptor shows low binding affinities for selective opioid agonists and antagonists. On the other hand, the ORL1 ligand nociceptin does not bind to the three traditional opioid receptors.The activation of the G protein-coupled ORL1 receptor inhibits adenlylate cyclase activity, reduces the intracellular concentration of the second messenger cAMP and regulates ion channels. The supraspinal administration of nociceptin produces hyperalgesia. unlike opioids. Spinal intrathecal and peripheral administration of nociceptin causes hyperalgesia in low doses and analgesia in high doses.The physiological role and detailed mechanisms of these dose-dependent nociceptin effects in opposite directions are not yet known.In addition, nociceptin modulates other biological phenomena such as feeding, locomotion, gastrointestinal function,memory, cardiovascular function,immunity, renal function, anxiety,dependence and tolerance.Future research on the physiological and pathophysiological importance of the nociceptin/ORL1 receptor systems may provide a target for novel therapeutics.     

Direct inhibition of the N-methyl-D-aspartate receptor channel by high concentrations of opioids.

BACKGROUND: Electrophysiologic and receptor binding studies showed that some opioids have noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist properties. METHODS: The effects and mechanisms of action of various opioid compounds were examined on four kinds of heteromeric NMDA receptor channels, namely the epsilon1/zeta1, epsilon2/zeta1, epsilon3/zeta1, and epsilon4/zeta1 channels, expressed in Xenopus oocytes. Furthermore, the action sites of opioids on NMDA receptor channels were investigated by site-directed mutagenesis. RESULTS: Meperidine inhibited four kinds of channels to a similar extent with inhibitor concentrations for half-control response (IC50s) of 210-270 microM. Morphine, fentanyl, codeine, and naloxone also inhibited NMDA receptor channels with affinities comparable to meperidine. Opioid inhibition exhibited voltage dependence and was quite effective at negative potentials. Opioids also shifted the inhibition curve of Mg2+ to the right. Furthermore, replacement of the conserved asparagine residue with glutamine in the channel-lining segment M2 of the zeta1 subunit, which constitutes the block sites of Mg2+ and ketamine, reduced the sensitivity to opioids, whereas that of the epsilon2 subunit barely affected the opioid sensitivity. CONCLUSIONS: These results, together with previous findings, suggest that the low-affinity NMDA receptor antagonist activity is a common characteristic of various opioid compounds, and that the inhibition is a result of channel-block mechanisms at the site, which partially overlaps with those of Mg2+ and ketamine. This antagonist property of opioids may be clinically significant in the spinal cord following epidural or intrathecal administration, after which the cerebrospinal fluid concentrations of some opioids reach the high micromolar level.     

The role of opioid receptor internalization and beta-arrestins in the development of opioid tolerance

Opioid tolerance, a phenomenon characterized by decreased analgesic effects obtained by the same dose of opioids after repeated use of the opioids, is a significant clinical problem. Traditional theory attributes receptor desensitization and internalization and post-receptor adaptation to the development of opioid tolerance. However, morphine, a commonly used opioid, induces tolerance but is not an effective drug to induce opioid receptor desensitization and internalization. Recent studies found that internalized opioid receptors can become competent receptors and recycle back to the cell surface membrane after dephosphorylation. Thus, receptor internalization may be a way to reduce opioid tolerance. Multiple studies have suggested a key role of beta-arrestins in opioid receptor desensitization and internalization and opioid tolerance. Although beta-arrestin 1 and beta-arrestin 2 are important for these effects induced by opioids with high intrinsic efficacy such as etorphine and fentanyl, morphine tolerance may be mediated mainly via beta-arrestin 2. Modification of opioid receptor internalization by affecting the interaction between opioid receptors and beta-arrestins may be a therapeutic target for reducing opioid tolerance.     

Ketamine in perioperative analgesia for knee surgeries: Review of evidence from randomized controlled trials

Successful perioperative analgesia for knee surgeries results in improved patient satisfaction and promotes successful rehabilitation. However, effective perioperative pain control is commonly a challenging task for knee surgeries. Such surgical procedures as total knee replacement or knee arthroscopy may be accompanied by severe postoperative pain. As opioids and nonsteroidal anti-inflammatory drugs are commonly used, the side effects of these types of medicines are quite common as well, especially in patients with chronic pain, as they are commonly dissatisfied with regular analgesia. Patients with chronic pain tend to have lower tolerance to pain, and be dependent and tolerant to opioids. These patients typically require higher doses of analgesics, which further negatively affect patients’ safety and the overall perioperative experience. Multimodal perioperative analgesia helps to spare opioids and promote successful rehabilitation. Ketamine is a noncompetitive N-Methyl-d-aspartate (NMDA) receptor antagonist that has been used for multimodal perioperative analgesia as an adjunct to opioids and nonsteroidal anti-inflammatory drugs. Despite the significant number of papers evaluating the role of ketamine in perioperative analgesia, the feasibility of ketamine for perioperative pain control in knee surgeries remains a subject of debate. There are only a limited number of high-quality studies on the topic. We used a systematic approach to evaluate randomized controlled trials with perioperative ketamine used for knee surgeries. The majority of the studies confirmed that the utilization of ketamine in perioperative analgesia was associated with lower pain scores, reduced opioid use, improved knee joint mobility, and an increase in patient tolerance for physical therapy and rehabilitation. The techniques for ketamine administration and dosing varied significantly, which may explain the inconsistencies between the reports. In addition, some of the studies, even those of high quality, used nitrous oxide in both the study and control groups. Nitrous oxide has NMDA receptor antagonist properties, as does ketamine. None of the studies reported whether patients were taking methadone, dextromethorphan, memantine, or magnesium sulfate, which are NMDA receptor antagonists too. The concomitant use of NMDA receptor antagonists, other than ketamine, may have interfered with the realization of analgesic effects of ketamine. Although it is largely accepted that NMDA receptor antagonism at the spinal level explains most of the analgesic effects of ketamine, it also interacts at other multiple receptors centrally, including, cholinergic receptors, nicotinic and muscarinic, adrenergic, central NMDA, and non-NMDA glutamate receptors. These influences may potentially explain why patients treated with other NMDA receptor antagonists had improved with ketamine as well. Ketamine also interacts with opioid receptors at supraspinal sites, where it produces supraspinal antinociception. Some of the studies did not report whether the participants were opioid naïve or opioid dependent. That might be an important determinant of the analgesic effect because opioid dependent patients are shown to benefit from the ketamine significantly. None of the examined randomized controlled trials assessed the effects of ketamine on opioid dependent patients. The variability between the outcomes of ketamine utilization for perioperative analgesia for knee surgeries might be, at least partially, explained by these findings.     

Intermittent lumbar puncture in rats: a novel method for the experimental study of opioid tolerance

Spinal subarachnoid opioid administration in rats has been a very important method for studying the pharmacological effects of opioids, including analgesia and tolerance. Intrathecal catheterization, either through the cervical or lumbar approach, has been the predominant method used to deliver opioids spinally. However, these methods have potential undesirable complications. To help mitigate these problems, we have developed a method of intermittent lumbar puncture in rats to study the effects of chronic spinal opioid administration. This method avoids catheter-associated morbidity. We demonstrate that this method can be readily used to induce spinal opioid tolerance without causing morbidity. Intermittent lumbar puncture should prove to be a useful technique for investigating mechanisms of spinal opioid analgesia and opioid tolerance development.     

Opioid mechanisms and opioid drugs

The opioid system comprises four receptor subtypes: μ (MOP), κ (KOP), δ (DOP), now called the ‘classical’ opioid receptors, and the ‘non classical’ nociceptin/orphanin FQ peptide (N/OFQ) receptor (NOP). Selective endogenous peptides, cleaved from larger precursor proteins, have been identified for all subtypes. Both classical and non-classical opioid receptors couple to inhibitory, pertussis toxin-sensitive G-proteins. Opioid receptors activate the same major intracellular pathways, which include: closing of voltage-sensitive calcium channels; opening of potassium channels and subsequent cellular hyperpolarization; and inhibition of cyclic adenosine monophosphate (cAMP) production through inhibition of the enzyme adenylate cyclase. All current, clinically used opioids work through activation of the MOP receptor. In an experimental setting, co-administration of MOP and DOP agonists has been shown to have a synergistic analgesic action. Administration of DOP-receptor antagonists has also been shown to reduce tolerance, physical dependence and other side effects of MOP-receptor agonists, without detriment to their analgesic action. In animal models NOP agonists are analgesic when administered spinally and have a pronociceptive/anti-analgesic (or anti-opioid) effect supraspinally. NOP knockout mice show a partial loss of tolerance to morphine and there is an up-regulation of N/OFQ production in chronic morphine tolerant mice. Analgesic tolerance that develops from repeated exposure to morphine is markedly attenuated in NOP knockout mice. The development of ligands with mixed action at MOP, DOP and NOP receptors offer new opportunities for opioid pharmacology.     

Potentiation of epidural opioids with epidural droperidol

During a period of one year, 119 patients with chronic pain received injections of opioids via a catheter inserted in the lumbar epidural space. Twenty-three patients (19%) showed evidence of tolerance and were given droperidol 1.25-5.0 mg epidurally. In 20 patients in this study, there was a significant reduction in the number of epidural opioid injections. Six patients complained of excessive sedation, which disappeared when the dose of droperidol was reduced, although this did not affect the analgesia. One patient given an accidental overdose of droperidol developed reversible Parkinsonism. It is concluded that epidural administration of the dopamine antagonist droperidol may be beneficial as supplementary medication to epidural opioids when tolerance develops.     

Perioperative Schmerztherapie bei opioidgewöhnten Patienten

In this review article the special anesthesiological problems of opioid tolerance and surgical interventions will be presented. These affect patients with a long-term opioid therapy of chronic pain, addicts with long-term substitution therapy and addicts with current or previous heroin addiction (“clean”). For all patient groups a guarantee of continuous and adequate analgesia (avoidance of fear and increasing patient compliance), exploiting suitable regional anesthesia or regional analgesia procedures when possible, and prevention of a physical opioid withdrawal syndrome have utmost priority. The necessary optimization of perioperative pain therapy only succeeds when based on a thorough preoperative examination of the clinical history which subtly inquires into the drug taking habits with respect to opioids and associated medications. Systemic and/or regional analgesia procedures are possible. Regional procedures are more effective for analgesia. Systemic analgesia procedures do not basically differ from those routinely used for patients without opioid tolerance. However, higher doses of opioids are necessary as well as individual titration according to needs. Special conditions apply to patients previously addicted to opioids (clean) when they are to be operated on. Non-opioids are sufficiently effective for low level pain and opiates can be avoided. Opioid therapy with inclusion of a non-opioid is necessary following major operations or for severe postoperative pain, even as i.v. patient-controlled analgesia (i.v. PCA) if needed. For these patients a relapse to addiction can be provoked by insufficient administration of analgesics, not by pain management including opioids.     

The roles of pain facilitatory systems in opioid tolerance

Opioids are powerful analgesic agents and have been widely used in clinical pain management for decades. Nevertheless, both acute and chronic opioids administration may produce tolerance, as indicated by a lowered responsiveness to the drugs at a later time. Koob and Bloom described two possible mechanisms of drug tolerance: a within-system and a between-systems adaptation. Opioid receptors uncoupling from G-proteins and receptor down-regulation, in particular the receptor's high affinity sites, are well-known mechanisms (the within-system) of opioid tolerance. A series of recent studies have proposed that a between-systems, particularly the pain facilitatory systems (opiate-activated opponent systems), may also involve in the development of opioid tolerance. Several lines of evidence suggest that N-methyl-D-asparate (NMDA) receptors activation and the subsequent nitric oxide (NO) production probably play a between-systems mechanism of opioid tolerance. Recently, our and others' studies also found that cyclooxygenase (COX) inhibitors could attenuate the opioid tolerance without enhancing morphine's antinociceptive effect. Taking all these findings together, the pain facilitatory systems included the NMDA-receptors, NO, and COX systems may also play important roles in opioid tolerance. In summary, except the opioid receptor uncoupling and opioid receptor down-regulation, chronic morphine treatment may also activate pain facilitatory systems (NMDA receptor activation, NO production, and COX ac-tivation) during opioid tolerance development. It implies that some complicated interactions may happen among the opioid receptor, NMDA-receptor, NO, and COX systems and are worth further investigations.     

Systemic analgesia and co-analgesia

Potent opioids are excellent painkillers but their use is hampered by side-effects such as nausea, vomiting, bowel dysfunction, urinary retention, pruritus, sedation and respiratory depression. Co-analgesics are often combined with opioids to reduce the prevalence of these unwanted effects while maintaining or even improve the quality of analgesia. A search of the recent literature demonstrated that peripheral opioid antagonists are able to reduce opioid-induced bowel dysfunction without interfering with analgesia. Dexmedetomidine, gabapentin, and ketamine significantly reduce opioid consumption but have no effect on the incidence of opioid side-effects. In contrast, intravenous lidocaine and corticosteroids not only produce an opioid-sparing but also a significant reduction in the occurrence of postoperative ileus and nausea and vomiting. It remains unclear whether the perioperative use gabapentin, ketamine and corticosteroids has an effect on the development of postsurgical chronic pain states.     

Acute pain management in patients receiving opioids for chronic and cancer pain

The number of patients receiving large doses of opioids presentingfor surgery is increasing as opioids gain a wider utilizationin the treatment of chronic pain. These patients need to beidentified before surgery because they may be tolerant to theeffects of opioids prescribed according to standard postoperativeanalgesic regimens designed for the opioid naive patient. Additionally,these patients may have developed a physical dependence on opioidsthat needs to be satisfied postoperatively. An insufficientdose may result in unrelieved pain and/or an opioid withdrawalreaction. In general, opioid tolerance, physical dependenceand withdrawal may be a significant problem in patients whohave been on high doses of weak opioids (e.g. codeine >120mg or tramadol >400 mg daily) or strong opioids (e.g. morphineor oxycodone) for >2 weeks preoperatively.     

Pain, opioid tolerance and sensitisation to nociception in the neonate

Pain is commonplace in newborn infants. Opioid analgesics have become increasingly used to reduce different types of pain in neonates, including pain from surgery, medical procedures and chronic conditions. Adverse effects of opioids include respiratory depression, hypotension and tolerance. These adverse effects can be minimised by utilising specific administration techniques and constant monitoring. Recent studies have demonstrated that untreated pain can have long-term effects on infant pain behaviours months beyond the events, thus, opioid analgesics may have a beneficial role that extends beyond the immediate painful event(s).     

Low dose alpha-2 antagonist paradoxically enhances rat norepinephrine and clonidine analgesia

Ultralow-dose opioid antagonists prolong opioid antinociception and block tolerance. In this study we determined whether low doses of the α-2 adrenergic receptor (A2-R) antagonist, atipamezole, similarly influenced A2-R-induced antinociception and tolerance. In rats, intrathecal norepinephrine (NE) or clonidine in combination with atipamezole was tested using tail-flick and paw pressure tests. Acute tolerance to NE was induced by serial injections. Low-dose atipamezole significantly prolonged NE and clonidine-induced antinociception. Coadministration of atipamezole with A2-R agonists also prevented loss of agonist potency in the acute tolerance model. This study demonstrates paradoxical effects of low-dose A2-R antagonists augmenting A2-R agonist-induced analgesia.