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Tiny doses of opioid could be first fast anti-suicide drug

By Gradois, Feb 5, 2016 | | |
  1. Gradois
    Tiny doses of opioid could be first fast anti-suicide drug

    Could a painkiller turn people away from suicide? A preliminary trial of an opioid called buprenorphine shows that the drug can reduce suicidal thoughts after just one week. If validated in larger studies, it could become the first fast-acting anti-suicide drug.

    Such a drug is sorely needed. The US Centers for Disease Control and Prevention (CDC) estimates that more than 9 million adults in the country reported having suicidal thoughts in 2013. Over a million went on to attempt suicide. “Around 400,000 suicidal people are coming to emergency rooms every year,” says Elizabeth Ballard at the National Institute of Mental Health. “Pharmacologically, nothing has been approved for acute treatment of suicidal ideation so anything that can help them is greatly needed.”

    When people seek help, they may be offered behavioural therapy or drugs such as antidepressants. But neither of these is guaranteed to alleviate feelings, and both can take six weeks or more to kick in. Ketamine, a drug being considered as an immediate treatment, can cause hallucinations and its effects wear off quickly. “Having something you could use on your own outside of a hospital would be beneficial,” says Ballard.
    Altered perception

    Jaak Panksepp at Washington State University and his colleagues decided to see whether an opioid can counter suicidal feelings. Opioids are one of the brain’s natural feel-good chemicals. They are released to relieve pain when we hurt ourselves, and are involved when we deal with mental pain, such as that caused by social rejection, a common trigger for suicidal thoughts. Recent studies have shown that the system seems to malfunction in people with depression. Separate work has shown that giving people low doses of opioids decreases their perception of social rejection. “Converging lines of evidence point to a connection between mental pain, depression, suicidal ideation and the body’s natural opioids,” says Panksepp.

    Panksepp’s team and collaborators at the University of Haifa in Israel gave very low doses of buprenorphine to 40 people identified as being severely suicidal – almost two-thirds of the group had already attempted to kill themselves. A second group received a placebo. The severity of the participants’ thoughts was measured every week for a month by a psychiatrist using a questionnaire. Half the participants were given their drug to take at home, the other half received it in the hospitals where they were staying for treatment.

    At the start of the month-long trial, the average score of the participants was about 20. People given buprenorphine dropped an average of six points after one week and nearly 10 points by the end. Participants given a placebo only dropped two points after the full month of treatment. To put this in context, a score of 20 is deemed worrying enough to hospitalise a person for their own safety. This wouldn’t be thought necessary for a score of 10.

    Twelve members of the study were unable to continue beyond the first week because they were so ill and two people – one from each group – attempted to end their lives during the trial. However, a week after the trial finished, everyone who had completed it reported no worsening of their condition.

    “Anything with effects even at the two week to month level would help a lot of people,” says Ballard. “I think it’s an exciting area of study.”
    Opioid abuse

    Panksepp says he’s confident that giving people higher doses of buprenorphine would have seen the effect kick in even earlier. Upping the dose is likely to be controversial, however, especially in the US, where the abuse of prescription opioids is so bad it is being called an epidemic. The latest information, from 2013, shows that across the country, 44 people died from overdoses of drugs such as OxyContin (oxycodone) each day.

    The danger with opioids is that taking too much can dampen a person’s breathing to lethal levels. Of all the opioids, buprenorphine carries the lowest risk because there’s a dose beyond which users get no additional pain-relief – or high. It is even prescribed to people who are addicted to other opioids. What’s more, the daily dosages Panksepp’s team administered were 30 times lower than the amount needed to create an addiction to the drug. No participants reported going through withdrawal once they stopped taking buprenorphine, suggesting that none became dependent on the drug during the study.

    “I think they’re onto something. However, buprenorphine acts on a number of different opioid receptors and it’s still unclear which one or ones are playing a role in the anti-suicidal effects,” says Joan Striebel, a psychiatrist with the California Department of State Hospitals. “I hope this work spurs more interest in what specific molecules could be involved in suicidal thought.”

    “As a psychiatrist I have spent the last 25 years of my life speaking to people who want to kill themselves on an almost daily basis. Studying and treating the neurochemistry may help us prevent broken lives,” says co-author Yoram Yovell of the Institute for the Study of Affective Neuroscience at the University of Haifa.

    Journal reference: The American Journal of Psychiatry, DOI: 10.1176/appi.ajp.2015.15040535

    Speak to your doctor before taking any medication.

    By Mallory Locklear
    New Scientist


  1. TheBigBadWolf
    Now its a widely known fact that theres nothing better (excuse the term) for anxiety, panic and dark thoughts than the puff on an opium.pipe or the sip on your bottle of laudanum.

    Why one would use a synthetic opioid that's not even a full agonist is beyond me.
    Can I have explanation from someone more knowledgeable, please?

  2. Iknownot
    The gold standard antisuicide drug is low dose (0.5-1 mg) risperidone. I dont buy that opiate mambo-jambo, but it is always good to see research into this topic.
  3. TheBigBadWolf
    See,Iknownot, it would be nice if you at least would mention why you don't buy into what you are calling a mumbo-jumbo and what this mumbo-jumbo is consisting of.

    Your,mentioning of risperidone as'gold standard' does also not explain what you are on about.
    For a discussion that's really poor and falls (imnsho) under the title "things better left unwritten".
    Its simply not enough to throw around some words that could mean all or nothing.

    I'm really sorry that I need to tell a fellow member that they are producing blah blah.

    Thanks for reading my offtopic post
  4. Iknownot
    A preliminary trial of an opioid called buprenorphine shows that the drug can reduce suicidal thoughts after just one week

    Ketamine, a drug being considered as an immediate treatment, can cause hallucinations and its effects wear off quickly

    The severity of the participants’ thoughts was measured every week for a month by a psychiatrist using a questionnaire.

    Do you see the problem?

    It is always good to question anything, it doesnt matter what the topic is about. Everybody knows that opiates make you feel like you dont give a shit, but do they have true antisuicidal properties ? I mean tianeptine is an opiate, but it is by far a miracle drug.

    They say buprenorphine can reduce suicidal thoughts after a week, but they continue the study for a whole month. It is a preliminary study, we need far more scientific evidence regarding the hypothesis.
    Ketamine only has antidepressant qualities in certain types of depression and its effects last for two weeks. How about buprenorphine? Did its effects lasted after cessation? There are so many questions unanswered, that is why I dont buy it yet.

    That is all I say and I believe you have the right to express your opinion.
  5. Weltmeister
    This is about preventing acute suicidal thoughts. For long term treatment opioid would be horrible because of their addiction potential. Thus its irrelevant if the effects last after cessation.
  6. Iknownot
    Well, if we want to prevent acute suicidal ideation than we would better find something that works faster than a month. Buprenorphine would be by no means a miracle drug and the first anti-suicide drug - the title of the article is so misleading.

    As I have already pointed out, there are already several drugs/methods studied/used for this condition, including NMDA antagonists, low-doses of atypical antipsychotics, ECT and so on.

    I believe that it is too much bias in the article above (a bit similar to the MDMA article). Again, the title of the above article is bit of an exaggeration.
  7. TheBigBadWolf
    What makes you think is horrible in addiction when it helps keeping people from killing themselves?
  8. tatittle
    Many of those pyschiatric medications have dependence issues too. Opiates would likely only lose effectiveness when someone ran out...which happens with all the pysch meds too..
  9. scartissue_68
    I have trouble with the article, but like BBW, I believe rejecting the premise of opiates being effective in controlling suicide, out of hand is irresponsible when discussing something so irreversible.

    The article says the Bupe was dosed to avoid addiction. That may be true for a test over the period of a month, but hardly an accurate statement. Just read some of the "Buprenorphine General Sharing" Thread for the breadth and depth of addiction caused by this drug. The article does not state the dosing used. Bupe is very potent by volume/weight and "30 times less than a dose used for addiction treatment" could mean a dose of 1mg (the equivalent of 25 mg of oral Morphine) which, if taken daily would most definitely become addicting.

    I can say from experience with just a small daily dose of Bupe from a BuTrans patch over the period of two years....it left me with about two weeks of minor withdrawals and terribly annoying, extended PAWS. I was only taking 15mcgm per hour, ever hour 24/7. That said, I withdrew Cold Turkey and most common anti-depressants also have a pretty nasty withdrawal profile when simply discontinued after long-term therapy.

    In favor of the article's general theme, Bupe is also being studied for its anti-depressant qualities. So, its not a big leap to believe it could help with suicide. Except for extreme, uncontrollable pain, I can not think of any circumstance wherein one who would commit suicide who isn't depressed (clinically or environmentally). This is a broad conclusion, but its not Mambo-Jambo.

    As is said for just about every drug...more research is needed.
  10. Calliope
    This research on low-dose buprenorphine for suicidal ideation is more careful, persuasive and promising than many responses I've seen in this thread seem to hold (as are a few other studies on related questions). There is in fact data indicating a number of things about opiate/oids, and buprenorphine specifically, that are very suggestive that it has potential as a treatment for depression, suicidal ideation, and even stress-related relapse in opiate/oid addiction.

    Why buprenorphine? Consider the following:

    From a recent case report (uploaded here: The Anti-Suicidal Potential of Buprenorphine: A Case Report. Int J Psychiatry Med. Note the causal role of cutting a pain patient off from thier pain meds [​IMG]):
    A change in primary care providers in conjunction with her urine toxicology results resulted in a decision to cease opioid treatment of chronic pain. Ms. S. began obtaining prescription opioids illicitly to treat her pain and would intermittently purchase heroin. She injected heroin for pain relief and “energy”. Then, in the context of ongoing depression and undertreated pain, she attempted to end her life by driving her car off a bridge and was psychiatrically hospitalized. A change in her antidepressant served to diminish depressive symptoms; yet, she continued to be plagued with thoughts of ending her life.
    But the patient has a very heartening and sustained response to induction onto buprenorphine:
    On return visit one week after induction, when asked about suicidal thoughts, Ms. S. paused and replied that they had completely disappeared. She affirmed that she hadn’t thought of ending her life in several days. In terms of cause, she cited a resolution of her depression, more energy, decrease in her pain, increased motivation and the ability to complete daily tasks. “I finally planted the flowers that I bought three months ago. That’s a big deal!” she exclaimed.

    On follow-up one month after buprenorphine/naloxone initiation, Ms. S. remained feeling well, with positive mood. Suicidal ideation remained absent. Three months post-induction, suicidality had not re-emerged. To date, all subsequent urine drug screens have been positive only for buprenorphine.​

    As to the study discussed in the OP (now uploaded to the DF archive here Ultra-Low-Dose Buprenorphine as a Time-Limited Treatment for Severe Suicidal Ideation: A Randomized Controlled Trial (2015) AJP in Advance), it begins by pointing out a simple motivation for their work--"no short-term pharmacological treatments that are suitable for independent outpatient use are currently available for suicidal ideation." The qualifications in that are key; the study's authors are perfectly aware of the usefulness of standard antidepressants (but also their delayed effectiveness), and of ketamine's rapid effectiveness (but also that it needs frequent administration in a medical context), as they are of the effective use of other agents like lithium and antipsychotics (in some patients) for suicidality.

    To specifically motivate the hypothesis that buprenorphine may be effective they tell us:

    "Depression, which is often accompanied by suicidal ideation, shares neurobiological and psychological characteristics with separation distress... Remarkably low, nonsedating doses of opioid analgesics have been found to inhibit separation distress in every animal species tested. The neuroanatomy of the separation distress system overlaps with the brain’s “pain matrix” and shares someof its neurotransmitter substrates. It has been suggested that abrupt cessation of opioid release upon separation from attachment figures contributes to painful separation feelings in animals and humans.

    Patients with borderline personality disorder, who are exquisitely sensitive to separations, often become suicidal after interpersonal rejections, and this patient population has been found to have abnormalities in their endogenous opioid systems. Among patients in psychotherapy, most suicidal acts occur after interpersonal losses or rejections, and analgesic treatment has been shown to decrease social pain in rejected lovers. Social rejection activates the endogenous opioid systemin healthy volunteers, and this activation is altered in depressed patients.

    Opioids were widely used to treat depression from about 1850 to 1956. Because of their addictive potential and lethality in overdose, opioids were replaced by standard antidepressants once these became available. However, several studies since then have found them to be effective for treating depression.

    In addition to their association with depression and separation distress, physical and mental pain are associated with suicidality. Some studies have found mental pain to be the psychological variable most strongly associated with current suicidality, more so than depression and hopelessness.

    In sum, converging lines of evidence point to a connection between separation distress, mental pain, depression, suicidal ideation, and endogenous opioids. It was therefore hypothesized that opioids in very low dosages might help alleviate suicidal ideation."​

    And it really looks like buprenorphine isn't simply cheering people up by making them high -- A recent study pretty convincingly shows there is something real going on beyond depressive symptoms being relieved that way (in the DF archive here. The emphases in the quotes below are my additions):

    Evaluation of Opioid Modulation in Major Depressive Disorder. Neuropsychopharmacology (2015) 40, 1448–1455; doi:10.1038/npp.2014.330; published online 14 January 2015
    Although opioids have known antidepressant activity, their use in major depressive disorder (MDD) has been greatly limited by risk of abuse and addiction. Our aim was to determine whether opioid modulation achieved through a combination of a μ-opioid partial agonist, buprenorphine (BUP), and a potent μ-opioid antagonist, samidorphan (SAM), would demonstrate antidepressant activity without addictive potential. A placebo-controlled crossover study assessed the opioid pharmacodynamic profile following escalating doses of SAM co-administered with BUP in opioid-experienced adults. A subsequent 1-week, placebo-controlled, parallel-group study was conducted in subjects with MDD and an inadequate response to standard antidepressant therapy. This second study evaluated safety and efficacy of ratios of BUP/SAM that were associated with partial and with maximal blockade of opioid responses in the initial study. Pupillometry, visual analog scale assessments, and self-reported questionnaires demonstrated that increasing amounts of SAM added to a fixed dose of BUP resulted in dose-dependent reductions in objective and subjective opioid effects, including euphoria and drug liking, in opioid-experienced adults. Following 7 days of treatment in subjects with MDD, a 1:1 ratio of BUP and SAM, the ratio associated with maximal antagonism of opioid effects, exhibited statistically significant improvement vs placebo in HAM-D17 total score (p ¼ 0.032) and nearly significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) total score (p ¼ 0.054). Overall, BUP/SAM therapy was well tolerated. A combination of BUP and SAM showed antidepressant activity in subjects with MDD. Balanced agonist–antagonist opioid modulation represents a novel and potentially clinically important approach to the treatment of MDD and other psychiatric disorders.​

    From the discussion in the paper:
    There are no prior published reports of placebo-controlled studies of opioid agonists in the treatment of depression. In observational studies, treatment with μ-opioid agonists has been associated with significant and rapid mood elevation in depression, including subjects with treatment-resistant MDD (Emrich et al, 1982; Kosten et al, 1990; Mongan and Callaway, 1990; Bodkin et al, 1995; Gerra et al, 2006; Nyhuis et al, 2008, Karp et al, 2014). It remains unknown whether these effects are simply attributable to the induction of drug liking or a ‘high.’ In other words, it is not known whether the addictive and antidepressant effects of opioids are intrinsically inseparable. If a co-administered μ antagonist was able to counteract the addictive properties of a μ agonist, without interfering with its antidepressant effects, then controlled opioid modulation via combined agonist–antagonist administration might serve as the basis for a novel pharmacotherapeutic approach with broader applicability in the treatment of MDD.

    To test this hypothesis, we utilized buprenorphine (BUP), a partial μ agonist. In addition to its effects on the μ-pioid receptor, BUP has also been shown to block the action of k agonists in in vivo pharmacology assays (Leander, 1987). BUP has shown evidence of antidepressant efficacy in MDD in observational studies (Bodkin et al, 1995; Nyhuis et al, 2008; Emrich et al, 1982; Cowan, 2003; Walsh et al, 1994, 1995; Callaway, 1996, Karp et al, 2014).
    Following the calibration of BUP and SAM in opioid-experienced adults, the second study evaluated the 8:1 and 1:1 dose ratios as adjunctive therapies in subjects with MDD who demonstrated inadequate response to SSRI or SNRI treatment. Antidepressant effects were greatest in subjects who received BUP and SAM at the 1:1 ratio, which was the ratio associated with maximal blockade of opioid effects. Thus, following 7 days of once daily BUP/SAM at a 1:1 ratio, subjects with MDD exhibited statistically significant improvement in HAM-D17 total score (p ¼ 0.032) and nearly significant improvement in MADRS total score (p ¼ 0.054) vs placebo. The magnitude of effect at 1 week with the 1:1 ratio was substantial, with an effect size of 1.49 and 1.29 for HAM-D17 and MADRS, respectively, using Cohen’s d (Cohen, 1988).
    The observation of robust antidepressant activity in subjects receiving the 1:1 ratio, ie, the ratio associated with maximal antagonism of μ-opioid effects, was surprising. It had been anticipated that the 8:1 ratio, which retains a larger degree of μ-opioid agonism than the 1:1 ratio, would demonstrate the greatest antidepressant response. Agonism of μ-opioid receptors has been correlated with increases in dopamine levels, enhancement of hedonic tone, and sense of contentment, which together would be expected to confer antidepressant activity (Lutz and Kieffer, 2013). Post mortem studies of patients with depression and suicide have shown evidence of increased μ-opioid receptor expression consistent with an endogenous endorphin insufficiency (Scarone et al, 1990; Gross-Isseroff et al, 1990; Gabilondo et al, 1995). Similarly, PET studies reveal multiple focal deficits in endogenous opioid activity in depressed patients and with induced sadness states compared with controls (Kennedy et al, 2006; Ribeiro et al, 2005; Bencherif et al, 2002; Zubieta et al, 2003).

    The robust antidepressant activity of the 1:1 ratio implies that substantial exogenous augmentation in μ-opioid agonist activity may not to be necessary to elicit a clinically meaningful response in the treatment of depression. Rather, our results indicate that simultaneous administration of an opioid agonist and antagonist with opposing pharmacologic activities of similar magnitude, ie, a ‘balanced’ agonist–antagonist opioid modulation, may be sufficient and optimal to normalize dysregulated or impaired endogenous opioidergic tone may in the context of depression, and hence yield therapeutic benefit.

    An alternative, but not mutually exclusive, explanation of these results invokes the κ-opioid system. In contradistinction to μ-receptor agonism, κ-receptor agonism has been associated with adverse effects on mood in humans (Pfeiffer et al, 1986; Wadenberg, 2003) and rodents (Carlezon et al, 2009; Mague et al, 2003). On the basis of the results in animal models, it has been proposed that a κ-opioid antagonist might function therapeutically as an antidepressant in humans (Knoll and Carlezon, 2010). In addition to its effects on the μ-opioid receptor, BUP has also been shown to block the action of κ agonists in in vivo pharmacology assays and has been characterized in vitro to be a κ partial agonist with low intrinsic activity (Leander, 1987; Wentland et al, 2009). Indeed, functional κ antagonism has been proposed as a mechanism underlying the efficacy of BUP/naltrexone combination therapy for opioid dependence (Gerra et al, 2006; McCann, 2008; Rothman et al, 2000). Further investigation in humans and animal model systems utilizing imaging, pharmacologic, and other probes will be needed to under-stand the relative contribution of endogenous dynorphin blockade and endogenous μ-opioid modulation to the observed antidepressant activity with BUP/SAM.

    Also relevant and interesting from a study on buprenorphine and stress (uploaded here Opioid partial agonist buprenorphine dampens responses to psychosocial stress in humans (2015) Psychoneuroendocrinology (2015) 52, 281—288):
    In this study, we assessed the effects of buprenorphine,a μ-opioid partial agonist, on physiological and subjective responses to a stressful speaking task in healthy human volunteers. In accordance with our hypothesis, we found that both doses of buprenorphine attenuated cortisol responses to the task and some measures of emotional stress (i.e., pre-task perceptions of threat and post-task ratings of satisfaction with their performance). This is the first study to show that an opioid drug reduces responses to acute psychosocial stress in a healthy human population, extending findings with laboratory animals and clinical populations showing that the opioid system is involved in mediating responses to stress.
    One important alternative interpretation of our results is that the effects of buprenorphine on stress may be mediated by its effects on reward, or feelings of euphoria. This is unlikely given the observation that the stress-blunting effects occurred even at the 0.2 mg dose, which did not produce significant ratings of ‘‘feel high’’. Another interpretation might be that the observed effects were secondary to more general sedation, but neither dose affected subjects’ performance on the task, suggesting that the stress-dampening effects were relatively specific.

    Buprenorphine is currently used sublingually in opioid replacementtherapy at doses ten to forty times those used in this study(4—16 mg sl). Here we showed that a relatively low dose(0.2 mg sl) of buprenorphine, one that does not produce euphoria, substantially reduces cortisol responses to stress. Interestingly, this stress-dampening effect may also be valuable during treatment for opioid users, to prevent relapse. Stress is a known precipitant of relapse in opioid addicts (Sinha, 2001; Lijffijt et al., 2014; Spanagel et al., 2014), and dysregulation of the HPA axis is a hallmark of opioid withdrawal (Zhang et al., 2008). While buprenorphine isused clinically at higher doses in opioid replacement therapy, our results suggest that even at low doses, the drug has stress-blunting effects that may contribute to its efficacy in preventing relapse in vulnerable populations.​
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