Posted by jerrympls on March 20, 2006, at 1:51:10
In reply to Re: opioids: How to get a script for depression? » pseudoname, posted by jedi on March 20, 2006, at 1:19:33
> How did you get an MD to give you a buprenorphine script for depression? Did they think they were prescribing it for opioid withdrawal? I can't even find any good studies to use to show my doctor. I'm open to any ideas.
Hey Jedi-- My doc prescribes me hydrocodone along with my other depression meds. Here are some abstracts that may help:
USE OF OPIATES FOR TREATMENT RESISTANT DEPRESSION
1: J Clin Psychiatry. 2001 Mar;62(3):205-6.
Treatment of refractory major depression with tramadol monotherapy.
Shapira NA, Verduin ML, DeGraw JD.
PMID: 11305709 [PubMed - indexed for MEDLINE]
2: Aust N Z J Psychiatry. 2000 Dec;34(6):1032-3.
The efficacy of intramuscular tramadol as a rapid-onset antidepressant.
PMID: 11127616 [PubMed - indexed for MEDLINE]
3: Am J Psychiatry. 1999 Dec;156(12):2017.
Treatment augmentation with opiates in severe and refractory major
Stoll AL, Rueter S.
PMID: 10588427 [PubMed - indexed for MEDLINE]
4: J Clin Psychopharmacol. 1999 Aug;19(4):373-6.
Long-term codeine use is associated with depressive symptoms.
Romach MK, Sproule BA, Sellers EM, Somer G, Busto UE.
Department of Pharmacology, Faculty of Pharmacy, University of Toronto,
for Addictions and Mental Health, Ontario, Canada.
A community survey was conducted among long-term (>6 months) users
of codeine-containing products to characterize chronic use of these
extensively consumed medications. Respondents recruited through newspaper
advertisements completed a mailed questionnaire. Three hundred thirty-nine completed questionnaires were obtained, yielding a response rate of 70%. Codeine dependence/abuse as defined by DSM-IV criteria was present in 41% of
the respondents. Two thirds of the subjects had sought help for mental
health problems, most often depression (70%). Scores on the Symptom
Checklist-90 subscales were modestly elevated, particularly on the Depression subscale (1.2 +/- 0.9). Long-term codeine use is strongly associated with dependence. Depression and depressive symptoms are common. These data suggest that dysphoric mood states may be significant in maintaining long-term codeine use.
PMID: 10440467 [PubMed - indexed for MEDLINE]
5: Biol Psychiatry. 1996 Jun 15;39(12):989-90.
Buprenorphine for depression: the un-adoptable orphan.
PMID: 8780832 [PubMed - indexed for MEDLINE]
6: Am J Psychiatry. 1996 Jun;153(6):843-4.
Mood alterations and tramadol.
Pinkofsky HB, Woodward RA, Reeves RR.
PMID: 8633712 [PubMed - indexed for MEDLINE]
7: J Am Osteopath Assoc. 1996 Mar;96(3):156.
Long-term narcotic use may complicate treatment for depression.
PMID: 8932590 [PubMed - indexed for MEDLINE]
8: Biomed Pharmacother. 1996;50(6-7):279-82.
Treatment of depressive syndromes in detoxified drug addicts: use of
Laqueille X, Bayle FJ, Spadone C, Jalfre V, Loo H.
Service Hospitalo-Universitaire de Sante Mentale et de Therapeutique,
Hospitalier Specialise Sainte-Anne, Paris, France.
Depressive syndromes are very frequent in drug-addicted patients. Their
study is particularly difficult on account of the toxic intake which disturbs
the clinical analysis. Methadone has improved our understanding of these
pathologies. In fact, methadone permits treatment of some depressive
disorders typically linked to addiction, such as a motivational symptoms and
depressive mood following intoxication. It brings to the fore the other mood
disorders which are often associated with drug intake.
PMID: 8952868 [PubMed - indexed for MEDLINE]
9: J Clin Psychopharmacol. 1995 Feb;15(1):49-57.
Buprenorphine treatment of refractory depression.
Bodkin JA, Zornberg GL, Lukas SE, Cole JO.
McLean Hospital, Consolidated Department of Psychiatry, Harvard Medical
Belmont, MA 02178, USA.
Opiates were used to treat major depression until the mid-1950s. The
advent of opioids with mixed agonist-antagonist or partial agonist activity, with
reduced dependence and abuse liabilities, has made possible the reevaluation of
opioids for this indication. This is of potential importance for the population
of depressed patients who are unresponsive to or intolerant of
conventional antidepressant agents. Ten subjects with treatment-refractory,
unipolar, nonpsychotic, major depression were treated with the opioid partial
agonist buprenorphine in an open-label study. Three subjects were unable to
tolerate more than two doses because of side effects including malaise, nausea,
and dysphoria. The remaining seven completed 4 to 6 weeks of treatment and as
a group showed clinically striking improvement in both subjective and
objective measures of depression. Much of this improvement was observed by the end of 1 week of treatment and persisted throughout the trial. Four subjects
achieved complete remission of symptoms by the end of the trial (Hamilton Rating
Scale for Depression scores < or = 6), two were moderately improved, and
one deteriorated. These findings suggest a possible role for buprenorphine
in treating refractory depression.
PMID: 7714228 [PubMed - indexed for MEDLINE]
10: J Subst Abuse Treat. 1990;7(1):51-4.
Depressive symptoms during buprenorphine treatment of opioid abusers.
Kosten TR, Morgan C, Kosten TA.
Department of Psychiatry, Yale University School of Medicine, New Haven,
Among 40 opioid addicts treated as outpatients with sublingual
buprenorphine (2-8 mg daily) for a month, depressive symptoms significantly decreased in the 19 who were depressed at intake to treatment.
PMID: 2313769 [PubMed - indexed for MEDLINE]
11: Int Clin Psychopharmacol. 1988 Jul;3(3):255-66.
Current and historical concepts of opiate treatment in psychiatric
Weber MM, Emrich HM.
Max-Planck-Institut fur Psychiatrie, Munchen, Federal Republic of
In recent years psychiatric research has rediscovered the theoretical
and clinical importance of opiates, especially for the understanding of
depressive disorders. However, opiate treatment is not a new therapeutic concept
in psychiatry. The use of opium for "melancholia" and "mania" may be traced to ancient classical medicine. After Paracelsus and Sydenham, the psychiatry of the German Romantic Era widely discussed therapeutic opium use with the Engelken family going on to develop a structured opium treatment of depression in the first half of the nineteenth century. Although the underlying scientific problems of psychiatric opium therapy were never solved, it gained an outstanding position as a practical treatment for over 100 years.
PMID: 3153713 [PubMed - indexed for MEDLINE]
Mice deficient for delta- and mu-opioid receptors
exhibit opposing alterations of emotional responses
Filliol D, Ghozland S, Chluba J, Martin M, Matthes HW,
Simonin F, Befort K, Gaveriaux-Ruff C, Dierich A,
LeMeur M, Valverde O, Maldonado R, Kieffer BL
 UPR 9050 CNRS,
ESBS Universite Louis Pasteur,
 These authors contributed equally to this work.
Nat Genet 2000 Jun; 25(2):195-200
The role of the opioid system in controlling pain, reward and addiction is well established, but its role in regulating other emotional responses is poorly documented in pharmacology. The mu-, delta- and kappa- opioid receptors (encoded by Oprm, Oprd1 and Oprk1, respectively) mediate the biological activity of opioids. We have generated Oprd1-deficient mice and compared the behavioural responses of mice lacking Oprd1, Oprm (ref. 6) and Oprk1 (ref. 7) in several models of anxiety and depression. Our data show no detectable phenotype in Oprk1-/- mutants, suggesting that kappa-receptors do not have a role in this aspect of opioid function; opposing phenotypes in Oprm-/- and Oprd1-/- mutants which contrasts with the classical notion of similar activities of mu- and delta-receptors; and consistent anxiogenic- and depressive-like responses in Oprd1-/- mice, indicating that delta-receptor activity contributes to improvement of mood states. We conclude that the Oprd1-encoded receptor, which has been proposed to be a promising target for the clinical management of pain, should also be considered in the treatment of drug addiction and other mood-related disorders.
Implication of endogenous opioid system
in the learned helplessness model of depression
Tejedor-Real P, Mico JA, Maldonado R,
Roques BP, Gibert-Rahola J
Department of Neurosciences,
School of Medicine, Cadiz, Spain
Pharmacol Biochem Behav 1995 Sep; 52(1):145-52
The involvement of opioid system on the learned helplessness model of depression was investigated. Animals preexposed to inescapable shocks were treated with either Met-enkephalin, Leu-enkephalin, morphine, imipramine, naloxone, RB 38A (a mixed inhibitor of enkephalin degrading enzymes), or RB 38B (a selective inhibitor of neutral endopeptidase EC 22.214.171.124). Stimulation of opioid system by either opioid agonists or enkephalin catabolism inhibitors reversed the escape deficit induced by shock pretreatment. In contrast, administration of naloxone potentiated the effect of inescapable shocks. Imipramine reduced the number of escape failures in this test, and this effect was antagonized by naloxone. These results point to the involvement of the endogenous opioid system in this model of depression.
Antimanic, antidepressant, and antipanic effects of opiates: clinical, neuroanatomical, and biochemical evidence
Gold MS, Pottash AC, Sweeney D, Martin D, Extein I
Ann N Y Acad Sci 1982; 398:140-50
These clinical data may offer some support for the hypothesis that opiates have antidepressant, antimanic, and antipanic effects. This hypothesis should be studied directly by double-blind studies of the effects of exogenous and synthetic endogenous opioid peptides in patients with major depressive illness, panic and anxiety states, schizophrenia, and schizo-affective illness. These clinical data support our studies in nonhuman primates and man which suggest a common LC or NE hyperactivity may underly both drug withdrawal and spontaneous panic states. Whether endorphin deficiency or derangements account for the postulated NE hyperactivity needs additional study and we will discuss our preliminary work later. Failure of endorphins to terminate bursts in LC firing rate and NE release may be responsible for both of these types of panic states. In addicts, this mechanism could exist prior to opiate use, or abuse of potent exogenous endorphinomentic compound may cause an endorphin-abnormality. Both of these possibilities would be compensated by continuous opiate maintenance. Methadone maintenance is a complicated psychiatric, psychological, and social phenomenon. Further studies are necessary to evaluate the role of opiate maintenance in treating or suppressing the emergence of underlying psychopathology. Previous psychiatric hospitalization or treatment for a schizophrenic or affective illness may contraindicate absolutely the use of clonidine or other rapid detoxification methods. These data suggest the possibility of substituting a nonaddicting psychotropic medication for opiates in some patients who are self-medicators. The clinical data support other data suggesting the potential antipsychotic, antidepressant, and antianxiety/antipanic effects of the endogenous opioids, endorphins, and exogenous opioids, endorphins, and exogenous opiates. These and other data suggest potential utility for opioid agonists and endorphin testing in psychiatric treatment and diagnosis.
The effect of naloxone on adrenocorticotropin and cortisol release: evidence for a reduced response in depression
Burnett FE, Scott LV, Weaver MG, Medbak SH, Dinan TG
Department of Psychological Medicine,
The Medical Colleges of St. Bartholomew's
and the Royal London Hospitals,
West Smithfield, UK.
J Affect Disord 1999 Jun; 53(3):263-8
BACKGROUND: Endogenous opioid peptides inhibit the hypothalamic-pituitary-adrenal (HPA) axis by influencing the release of hypothalamic corticotropin releasing factors. This study examines whether increased activity of the HPA axis in major depression is associated with reduced opioid tone. METHODS: We measured the adrenocorticotropin (ACTH) and cortisol responses to an intravenous bolus of naloxone 0.125 microg/kg in 13 depressed outpatients and 13 healthy volunteers. RESULTS: The mean cortisol response was significantly reduced (P<0.05), and the ACTH response was also non-significantly reduced in the depressed subjects. CONCLUSIONS: These findings imply that the degree of inhibitory endogenous opioid tone is reduced in depression. Various mechanisms for the finding are discussed, including possible alteration in the function of alpha-adrenergic pathways. CLINICAL IMPLICATIONS: Reduced endogenous opioid tone may explain why some depressed individuals self-medicate with opiates, and depression is associated with opiate withdrawal. Opioid pathways may have a role in the mechanism of action of antidepressant drugs, and may be of relevance in the development of novel antidepressants. LIMITATIONS OF THE STUDY: The sample size was small, leading to a failure of the difference of the basal cortisol levels and also the delta ACTH between the groups to reach statistical significance.
Opioid receptor types and dependence
Suzuki T; Misawa M
Department of Pharmacology,
School of Pharmacy,
Hoshi University, Tokyo, Japan.
Nippon Yakurigaku Zasshi, 1997 Apr, 109:4, 165-74
The existence of mu, delta and kappa opioid receptors in the central nervous system is well documented. The present review focuses on the relationships between opioid receptor types and physical and psychic dependences. Mu and delta, but not kappa opioid receptor agonists produce physical dependence. From behavioral, biochemical and molecular biological studies, it is suggested so far that development of physical dependence on morphine results predominantly from an activation of mu 1 and mu 2 opioid receptors which causes functional changes in Gi/o, adenylate cyclase, protein kinases A and C, beta-adrenoceptor and NMDA receptor in the locus coeruleus. Recently, there have been significant advances in studies on psychic dependence. Mu and delta opioid receptor agonists produce psychic dependence, but kappa opioid receptor agonists rather produce an aversive effect. Activation of the mesolimbic dopamine system may lead to psychic dependence on opioids. Mu and delta 1 opioid receptor agonists activate the mesolimbic dopamine system to induce a rewarding effect, whereas the rewarding effect of delta 2 opioid receptor agonists may be produced through a non-dopaminergic system. There are complicated interactions among opioid receptor types. The activation of kappa opioid receptor suppresses physical and psychic dependences on mu and delta opioid receptor agonists, but the activation of delta opioid receptor potentiates the dependence on mu opioid receptor agonists. The clinical use of morphine in patients with cancer pain won't develop dependence probably due to the balance of the opioid system coming from these interactions.
Outcome of chronic opioid
therapy for non-cancer pain
Haythornthwaite JA, Menefee LA,
Quatrano-Piacentini AL, Pappagallo M
Department of Psychiatry and Behavioral Sciences,
Johns Hopkins University School of Medicine,
Baltimore, Maryland, USA.
J Pain Symptom Manage 1998 Mar; 15(3):185-94
Potential iatrogenic mood and cognitive declines associated with long-acting opioid therapy were examined in 19 patients receiving long-acting oral opioid medications and compared to ten patients receiving usual care. Pain, mood, and cognitive function were measured before and after achieving stable doses. In addition to reducing pain, long-acting opioid medication reduced anxiety and hostility. No declines in cognitive function were associated with the long-acting opioid medications, and the group receiving long-acting opioid medications showed significant improvement on a measure of psychomotor speed and sustained attention. Both patient groups reported significant reductions in perceived impairment in daily activities due to pain. Treatment responders taking long-acting opioid medications (63%) were taking a significantly lower dose at follow-up than the treatment non-responder group. These findings suggest that long-acting opioid medications can improve mood and do not impair cognitive functioning in patients with chronic non-cancer pain.
Fentanyl and morphine, but not remifentanil, inhibit acetylcholine release in pontine regions modulating arousal
Mortazavi S, Thompson J, Baghdoyan HA, Lydic R
Department of Anesthesia,
The Pennsylvania State University,
College of Medicine,
Hershey 17033-0850, USA.
Anesthesiology 1999 Apr; 90(4):1070-7
BACKGROUND: Opioids inhibit the rapid eye movement (REM) phase of sleep and decrease acetylcholine (ACh) release in medial pontine reticular formation (mPRF) regions contributing to REM sleep generation. It is not known whether opioids decrease ACh release by acting on cholinergic cell bodies or on cholinergic axon terminals. This study used in vivo microdialysis to test the hypothesis that opioids decrease ACh levels at cholinergic neurons in the laterodorsal tegmental nuclei (LDT) and LDT axon terminals in the mPRF. METHODS: Nine male cats were anesthetized with halothane, and ACh levels within the mPRF or LDT were assayed using microdialysis and high-pressure liquid chromatography (HPLC). ACh levels were analyzed in response to dialysis of the mPRF and LDT with Ringer's solution (control), followed by dialysis with Ringer's solution containing morphine sulfate (MSO4) or naloxone. ACh in the mPRF also was measured during either dialysis delivery or intravenous infusion of remifentanil and during dialysis delivery of fentanyl. RESULTS: Compared with dialysis of Ringer's solution, microdialysis with MSO4 decreased ACh by 23% in the mPRF and by 30% in the LDT. This significant decrease in ACh was antagonized by naloxone. MSO4 and fentanyl each caused a dose-dependent decrease in mPRF ACh when delivered by dialysis. Remifentanil delivered by continuous intravenous infusion or by dialysis into the mPRF did not alter mPRF ACh. CONCLUSIONS: Morphine inhibits ACh at the cholinergic cell body region (LDT) and the terminal field in the mPRF. ACh in the mPRF was not altered by remifentanil and was significantly decreased by fentanyl. Thus, MSO4 and fentanyl disrupt cholinergic neurotransmission in the LDT-mPRF network known to modulate REM sleep and cortical electroencephalographic activation. These data are consistent with the possibility that inhibition of pontine cholinergic neurotransmission contributes to arousal state disruption by opioids.
Selective mu and delta, but not kappa, opiate receptor antagonists inhibit the habituation of novelty-induced hypoalgesia in the rat
Spreekmeester E, Rochford J
Douglas Hospital Research Center,
Department of Psychiatry,
Verdun, Quebec, Canada.
Psychopharmacology (Berl) 2000 Jan; 148(1):99-105
RATIONALE: There is now extensive evidence demonstrating that exposure to novel stimuli induces hypoalgesia and that this effect habituates over repeated exposure to the stimuli. Moreover, it has been shown that administration of the nonselective opiate receptor antagonist naloxone can attenuate the rate of habituation of novelty-induced hypoalgesia. OBJECTIVES: The present experiments were conducted to determine the relative influence of different opiate receptor subtypes in the attenuation of the habituation of novelty-induced hypoalgesia. METHODS: In experiments 1-3, different groups of male, Wistar rats (275-300 g) were administered vehicle, 0. 5, 1.0 or 2.0-nmol doses of the mu-selective antagonist Cys(2)-Tyr(3)-Orn(5)-Pen(7)-amide (CTOP), the delta-receptor selective antagonist naltrindole, or the kappa-selective antagonist nor-binaltorphimine (nor-BNI). In experiment 4, animals were administered vehicle, 5, 25 or 75-nmol doses of nor-BNI. All injections were delivered to the right lateral ventricle 30 min prior to exposure to a novel hot-plate apparatus (48.5 degrees C), once a day for eight consecutive days. RESULTS: Paw-lick latencies in vehicle-treated animals were long during the initial exposures and declined over repeated tests, suggesting the habituation of novelty-induced hypoalgesia. The rate of habituation was significantly attenuated by administration of 1.0-nmol and 2.0-nmol doses of CTOP, by a 2.0-nmol dose of naltrindole, but was unaffected by all doses of nor-BNI. CONCLUSIONS: These results support the involvement of the mu and delta, but not the kappa, opiate receptor subtypes in the habituation of novelty-induced hypoalgesia.
Reversal of learned helplessness by morphine in rats: involvement of a dopamine mediation
Besson A, Privat AM, Eschalier A, Fialip J
Laboratoire de Pharmacologie,
Faculte de Pharmacie,
Pharmacol Biochem Behav 1998 Jun; 60(2):519-25
The aim of this study was to examine the role of dopamine neurotransmission in the effects of morphine in the learned helplessness paradigm in rats, a generally recognized model of depression. In this model, rats first exposed to inescapable shocks (stressed rats) exhibited an escape deficit in a subsequent shuttle-box test performed 48 h later for 3 consecutive days. The numbers of escape failures and intertrial crossings (motor activity during each intertrial interval) were recorded. Morphine was injected twice daily for 5 days (6 mg/kg/day, s.c.), and haloperidol, a preferential D2-dopamine receptor antagonist, was injected i.p. 15 min before each shuttle-box session. At the highest dose tested (150 microg/kg) haloperidol mimicked the behavioral deficit produced by inescapable shocks. A 37.5 microg/kg dose of haloperidol, which was ineffective by itself, reversed the morphine-induced improvement of escape behavior in previously stressed rats and the morphine-induced increase in intertrial activity in both stressed and nonstressed animals. These results support roles (a) for a dysregulation of dopaminergic neuronal activity in the expression of escape deficit subsequent to an inescapable aversive situation, and (b) for a dopaminergic mediation in the effects of morphine in the learned helplessness paradigm.
Antidepressant-like effects of kappa-opioid
receptor antagonists in the forced swim test in rats
Mague SD, Pliakas AM, Todtenkopf MS,
Tomasiewicz HC, Zhang Y, Stevens WC Jr,
Jones RM, Portoghese PS, Carlezon WA Jr.
Behavioral Genetics Laboratory,
Department of Psychiatry,
Harvard Medical School,
McLean Hospital, Belmont,
Massachusetts 02478, USA.
J Pharmacol Exp Ther. 2003 Apr;305(1):323-30
We showed previously that cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) of rats regulates immobility in the forced swim test (FST), an assay used to study depression. Because CREB regulates expression of dynorphin (which acts at kappa-opioid receptors) in NAc neurons, these findings raised the possibility that kappa-receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the kappa-antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at kappa-receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar kappa-antagonists: 5'-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment, and 5'-acetamidinoethylnaltrindole (ANTI), which was potent and effective after systemic treatment. The behavioral effects of the kappa-antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the kappa-agonist [5alpha,7alpha,8beta]-N-methyl-N-[7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec8-yl]-benzenacetamide (U-69593) dose dependently increased immobility in the FST, consistent with prodepressant-like effects. The effects of the kappa-ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective kappa-antagonist (ANTI) did not affect the rewarding impact of lateral hypothalamic brain stimulation at a dose with strong antidepressant-like effects. These findings are consistent with the hypothesis that CREB-mediated induction of dynorphin in the NAc "triggers" immobility behavior in the FST. Furthermore, they raise the possibility that kappa-antagonists may have efficacy as antidepressants, but lack stimulant or reward-related effects.
Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability
Crain SM, Shen KF.
Department of Neuroscience,
Albert Einstein College of Medicine,
Yeshiva University, Bronx, New York, USA.
Pain 2000 Feb;84(2-3):121-31
Recent preclinical and clinical studies have demonstrated that cotreatments with extremely low doses of opioid receptor antagonists can markedly enhance the efficacy and specificity of morphine and related opioid analgesics. Our correlative studies of the cotreatment of nociceptive types of dorsal-root ganglion neurons in vitro and mice in vivo with morphine plus specific opioid receptor antagonists have shown that antagonism of Gs-coupled excitatory opioid receptor functions by cotreatment with ultra-low doses of clinically available opioid antagonists, e.g. naloxone and naltrexone, markedly enhances morphine's antinociceptive potency and simultaneously attenuates opioid tolerance and dependence. These preclinical studies in vitro and in vivo provide cellular mechanisms that can readily account for the unexpected enhancement of morphine's analgesic potency in recent clinical studies of post-surgical pain patients cotreated with morphine plus low doses of naloxone or nalmefene. The striking consistency of these multidisciplinary studies on nociceptive neurons in culture, behavioral assays on mice and clinical trials on post-surgical pain patients indicates that clinical treatment of pain can, indeed, be significantly improved by administering morphine or other conventional opioid analgesics together with appropriately low doses of an excitatory opioid receptor antagonist.
The cognitive and psychomotor effects of morphine in healthy subjects: a randomized controlled trial of repeated (four) oral doses of dextropropoxyphene, morphine, lorazepam and placebo
O'Neill WM, Hanks GW, Simpson P, Fallon MT, Jenkins E, Wesnes K
Department of Palliative Medicine,
Bristol Oncology Centre, Bristol, UK.
Pain 2000 Mar; 85(1-2):209-15
Ten healthy subjects (four male) of mean age 31 years (range 25-40) took part in a randomized double-blind four-way crossover study to examine the cognitive and psychomotor effects of repeated oral doses of dextropropoxyphene and morphine. Four treatments were compared: dextropropoxyphene napsylate 100 mg, morphine sulphate 10 mg, lorazepam 0.5 mg and placebo. Four doses of each drug were given at 4-h intervals to each subject on four separate study days at least 1 week apart. Cognitive function was assessed using choice reaction time, number vigilance, memory scanning, immediate and delayed word recall, word recognition, picture recognition, critical flicker fusion threshold (CFFT) and subjective measures of alertness, calmness and contentment. Lorazepam impaired the speed of responding on all tasks in which speed was recorded (except digit vigilance) and increased subjective ratings of calmness. Morphine had one major effect, which was to increase the accuracy of responding on the choice reaction time task, at every assessment. Morphine produced some sporadic effects in other tests and an increase in subjective calmness. Dextropropoxyphene impaired performance on choice reaction time and picture recognition. These data show that oral morphine may enhance performance in some measures of cognitive function, whereas dextropropoxyphene (in usual therapeutic doses) seems more likely to cause impairment. Neither opioid has substantial effects on cognition and psychomotor function compared with lorazepam.
Involvement of delta- and mu-opioid receptors
in the potentiation of brain-stimulation reward
Duvauchelle CL, Fleming SM, Kornetsky C
Boston University School of Medicine,
Laboratory of Behavioral Pharmacology,
MA 02118, USA.
Eur J Pharmacol 1996 Dec 5; 316(2-3):137-43
A rate-free method of determining brain-stimulation reward thresholds was used to identify the rewarding effects of the delta-opioid receptor and mu-opioid receptor agonist peptides, [D-Pen2, D-Pen5]enkephalin (DPDPE) and [D-Ala2-MePhe4-Gly(o1)5]enkephalin (DAMGO). The nucleus accumbens-delivered opioid receptor agonists produced marked lowering of the threshold for ventral tegmental area brain-stimulation reward. No change in baseline thresholds was seen after peripheral administration of the nonpeptide delta-opioid receptor antagonist, naltrindole. However, an unexpected finding was that naltrindole blocked the threshold-lowering effects of both DPDPE and DAMGO. These data demonstrate nucleus accumbens activation of delta- and mu-opioid receptors and ventral tegmental area brain-stimulation reward share common brain substrates. In addition, the interference of both delta- and mu-opioid receptor mediated reward by naltrindole may have implications for therapeutic use.
Behavioral effects of delta-opioid receptor
agonists: potential antidepressants?
Broom DC, Jutkiewicz EM, Rice KC, Traynor JR, Woods JH.
Department of Pharmacology,
University of Michigan Medical School,
Ann Arbor 48109-0632, USA.
Jpn J Pharmacol 2002 Sep;90(1):1-6
The development of selective delta-opioid receptor agonists has revealed some very intriguing behavioral properties. delta-Opioid agonists have antinociceptive, seizuregenic and convulsive properties. A number of studies have identified a novel behavioral effect of delta-opioid-receptor agonists, implicating a role for the delta-opioid receptor in depression. Early clinical experiments demonstrated that exogenously administered opioid peptides had antidepressant activity in human patients. Also, enkephalinase inhibitors, which prevent the degradation of endogenous enkephalins, produced antidepressant-like effects mediated through the delta-opioid receptor in animal models of depression. More recently, the selective non-peptidic delta-opioid agonists SNC80 and (+)BW373U86 demonstrated antidepressant-like activity in the forced swim assay in rats. These studies propose that the delta-opioid receptor may provide a new therapeutic target for treating human depression.
Tramadol induces antidepressant-type effects in mice
Rojas-Corrales MO, Gibert-Rahola J, Mico JA
Department of Neuroscience,
Faculty of Medicine,
University of Cadiz, Spain.
Life Sci 1998; 63(12):PL175-80
Tramadol is a clinically-effective, centrally-acting analgesic. This drug is a racemic mixture of two enantiomers, each one displaying different mechanisms: (+)tramadol displays opioid agonist properties and inhibits serotonin reuptake while (-)tramadol inhibits preferentially noradrenaline reuptake. The action of tramadol on the monoaminergic reuptake is similar to that of antidepressant drugs. Therefore, we have examined the effects of (+/-)tramadol, (+)tramadol and (-)tramadol in a test predictive of antidepressant activity, the forced swimming test in mice. Both (+/-)tramadol and its (-) enantiomer displayed a dose-dependent reduction on immobility; while the effect induced by the (+) enantiomer was not significant. Inhibition of noradrenaline synthesis, but not of serotonin synthesis, was capable of blocking the effect of (+/-)tramadol. The alpha-adrenoceptor antagonist phentolamine, as well as the alpha2-adrenergic antagonist yohimbine, and the beta-adrenoceptor blocker propranolol countered the immobility-reducing action of (+/-)tramadol. Moreover, neither the serotoninergic blocker methysergide nor the opioid antagonist naloxone antagonized the effect of (+/-)tramadol. Our results show that (+/-)tramadol and (-)tramadol have antidepressant-like effect in mice, probably mediated by the noradrenergic system rather than the serotoninergic or opioidergic ones.
Effects of chronic tramadol on pre- and post-synaptic
measures of monoamine function
Hopwood SE, Owesson CA, Callado LF, McLaughlin DP, Stamford JA.
Academic Department of Anaesthesia and Intensive Care,
St Bartholomew's and The Royal London School of Medicine and Dentistry,
Royal London Hospital, Whitechapel, UK.
J Psychopharmacol 2001 Sep;15(3):147-53
The atypical analgesic tramadol has strong structural similarities to the antidepressant venlafaxine and is a mixed noradrenaline (NA) and serotonin (5-HT) uptake inhibitor. Because tramadol has been found active in the forced swim test, a common predictor of antidepressant efficacy, we therefore examined the effects of chronic tramadol on various pre- and post-synaptic monoamine measures. Male Wistar rats (150-200 g) received tramadol (20 mg/kg i.p.) or vehicle for 21 days and were sacrificed 24 h after the last dose. Quantitative autoradiography revealed that specific frontocortical [3H]dihydroalprenolol and [3H]ketanserin binding was lower in the chronic tramadol group than controls (beta: 37+/-8 and 217+/-56 fmol/mg; 5-HT2A: 23+/-3 and 44+/-7 fmol/mg, respectively, p < 0.05). Chronic tramadol had no effect on the magnitude of electrically stimulated noradrenaline (NA) efflux or uptake in locus coeruleus (LC) slices. Although dexmedetomidine (10 nM) decreased LC NA efflux equally (by approximately 60%) in chronic tramadol and vehicle groups, desipramine (50 nM) increased LC NA efflux more in vehicle (to 164+/-7%) than tramadol-treated rats (144+/-6%; p < 0.05). Chronic tramadol had no effect on dorsal raphe (DRN) or median raphe (MRN) 5-HT efflux. However, 5-HT uptake in tramadol-treated rats was slower (p < 0.05) in MRN and nearly so (p = 0.055) in DRN. The selective 5-HT1A agonist 8-OH-DPAT reduced 5-HT efflux in both DRN and MRN. Its effect in DRN was greater in rats given chronic tramadol than in vehicle controls (54+/-2 versus 32+/-6% reduction in 5-HT efflux, respectively). In conclusion, we suggest that tramadol has many of the pre- and postsynaptic neurochemical features of a conventional antidepressant, as might be predicted from its pharmacology.
Eur Neuropsychopharmacol. 2001 Jun;11(3):215-20.
The prolactin response to sulpiride in major depression: the role of the D2 receptor in depression.
Verbeeck WJ, Berk M, Paiker J, Jersky B.
Department of Psychiatry, University of the Witwatersrand, Johannesburg, South Africa.
Multiple lines of investigations have implicated the role of the dopaminergic system in depression. The aim of the study was to characterise the Dopamine D2 receptor sensitivity status in depressed patients versus controls by means of a novel neuro-endocrine challenge test, the prolactin response to sulpiride. In this intervention, ten patients and ten age matched male volunteers were studied. The patients were diagnosed according to DSM-IV criteria, and Montgomery Asberg and Zung scales were done. There was no significant difference in baseline levels of prolactin between the depressed and control groups. Significantly higher prolactin levels after sulpiride challenge were however found in depressed patients than controls at all time points after sulpiride administration. This neuroendocrine challenge paradigm suggests that the prolactin response to sulpiride, a D2 receptor antagonist, is enhanced in depression, which suggests that this receptor might be supersensitive in depression compared to controls. This adds to the data implicating the dopaminergic system in the pathophysiology of depression, and suggests that dopaminergic mechanisms might be a target of therapeutic interest.
PMID: 11418281 [PubMed - indexed for MEDLINE]
1: Psychoneuroendocrinology. 1988;13(5):397-408.
Human studies on the mu opiate receptor agonist fentanyl: neuroendocrine and behavioral responses.
Hoehe M, Duka T, Doenicke A.
Psychiatric Hospital, University of Munich, F.R.G.
The neuroendocrine and behavioral responses to the potent mu opiate receptor agonist Fentanyl (FE) have been systematically investigated in healthy male volunteers. These volunteers received, according to a randomized block design, different doses of FE: 0.1 mg/70 kg (n = 11), 0.2 mg/70 kg (n = 11), 0.25 mg/70 kg (n = 8), and saline (n = 11). FE induced a pronounced dose-dependent increase of plasma prolactin concentrations, which was significant at the lowest dose. In contrast, growth hormone was significantly stimulated by the highest FE dose only. Moreover, FE induced a maximum reduction of plasma cortisol concentrations at the lowest dose (0.1 mg/70 kg). In parallel, marked euphoric responses were also observed at this lowest FE dose. These results suggest a mu specific influence on all neuroendocrine and behavioral parameters investigated. Different responses of these parameters to different doses of FE, however, suggest a differential modulation of these parameters by the mu receptor agonist FE.
• Clinical Trial
• Randomized Controlled Trial
PMID: 2849775 [PubMed - indexed for MEDLINE]
1: J Clin Psychiatry. 2001 Mar;62(3):205-6.
Treatment of refractory major depression with tramadol monotherapy.
Shapira NA, Verduin ML, DeGraw JD.
• Case Reports
PMID: 11305709 [PubMed - indexed for MEDLINE]
Prog Neuropsychopharmacol Biol Psychiatry. 2001 Feb;25(2):457-62.
Dose-dependent augmentation effect of bromocriptine in a case with refractory depression.
Wada T, Kanno M, Aoshima T, Otani K.
Department of Neuropsychiatry, Yamagata University School of Medicine, Japan.
1. A 52-year-old female with refractory depression had not responded to various treatments including electroconvulsive therapy and augmentation therapy with lithium or triiodothyronine. 2. Addition of bromocriptine 2.5-5 mg/day to imipramine improved her depressive symptoms. However, when the dose was increased to 15 mg/day to treat residual depressive symptoms, her clinical status deteriorated and returned to the original level. The dose reduction to 5mg/day again improved her depressive symptoms. 3. This report confirms the augmentation effect of bromocriptine for refractory depression. It also suggests that there is dose-dependency in this effect.
• Case Reports
PMID: 11294489 [PubMed - indexed for MEDLINE]
1: Ann Clin Psychiatry. 2000 Sep;12(3):137-40.
Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review.
Sporn J, Ghaemi SN, Sambur MR, Rankin MA, Recht J, Sachs GS, Rosenbaum JF, Fava M.
Department of Psychiatry, Massachusetts General Hospital, USA. spornj@intra.NIMH.NIH.GOV
OBJECTIVE: To assess the effectiveness and safety of pramipexole as an adjunctive medication in refractory bipolar and unipolar depression in a naturalistic setting. METHODS: Retrospective chart review by psychiatrists on staff at a university hospital identified all patients who had received pramipexole. Response was based on moderate to marked improvement in the Clinical Global Impression-Improvement (CGI-I) scale. RESULTS: Pramipexole (mean dose 0.70 mg/d, mean duration 24.4 weeks) was effective in 6/12 (50.0%) of patients with bipolar depression, and 8/20 (40%) of patients with unipolar depression, mean duration of follow-up of 24.4 weeks. One case of transient hypomania was noted. Eight patients discontinued pramipexole due to lack of response and four due to side effects. CONCLUSIONS: Pramipexole, used as an adjunct to antidepressants or mood stabilizers, appeared to be effective and safe in the treatment of unipolar and bipolar depression. These uncontrolled, retrospective, naturalistic pilot data require confirmation by controlled research before conclusions can be made.
PMID: 10984002 [PubMed - indexed for MEDLINE]
1: Adv Biochem Psychopharmacol. 1982;32:77-84.
A possible role of opioid substances in depression.
PMID: 7046369 [PubMed - indexed for MEDLINE]