28 Matching Annotations
  1. Last 7 days
    1. The impact of this exclusion itself is impossible to measure, but increasing meritocratic inequality has coincided with the opioid epidemic, a sharp increase in “deaths of despair,” and an unprecedented fall in life expectancy concentrated in poor and middle-class communities.

      Are these all actually related to meritocratic inequality? What other drivers might there be?

  2. May 2021
    1. Conclusion: The combination of ultra-low-dose naltrexone and morphine in extremity trauma does not affect the opioid requirements; it, however, lowers the risk of nausea.

      From the full text, they used 5 micrograms of naltrexone. Naltrexone dose is very finicky. There's low dose (LDN), very low dose (VLDN), and ultra-low dose (ULDN). This is a ULDN. I believe the type of effects I'm looking for occur at VLDN and LDN doses. If I recall correctly, I think 2 mg is optimal for analgesia, but I don't remember whether this was with or without morphine. 0.125 mg and 0.25 mg are effective in opioid withdrawal when combined with methadone. Thus, it's not too surprising that 5 mcg had little effect. At those doses, the effects it does have are like mediated by different mechanisms.

    1. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference.

      This is important because it suggests mood-brightening. Contrast this with combining L-type calcium channel blockers with opioids, which appears to limit tolerance to opioid analgesia that does not correspond to mood brightening.

  3. Apr 2021
    1. However, coadministration of nefiracetam (5 or 10 mg/kg, p.o.), enprofylline (30 mg/kg, p.o.) and rolipram (0.3 or 1 mg/kg, i.p.) with morphine during the pretreatment period, significantly reduced the withdrawal signs, moreover, the tolerance was significantly attenuated.

      Looks promising. It's odd that theophylline had a lesser effect.

    1. Conclusion: Our data suggest that the combination of VLF with morphine may be a relevant therapeutic implication to manage pain even when tolerance to morphine exists. Moreover, our data demonstrates the involvement of L-Arg/NO/cGMP pathway in the prevention of morphine tolerance and dependence by venlafaxine.

      It's not clear if this has relevance to the subjective effects. I'm starting to think that I won't get an answer anytime soon.

    1. Results: The administration of sildenafi l reduced all of the morphine withdrawal symptoms.

      An acute effect. Interesting but not particularly consequential. It does mean, however, that I need to be wary of studies using withdrawal as a netric when combining PDE5 inhibitors with opioids.

    1. Results: Tadalafil showed anti-nociceptive effect when given alone at different doses (p<0.05). However, tadalafil significantly decreased the analgesic effect of morphine (p<0.05). In addition, tadalafil significantly increased the tolerance to morphine (p<0.05). Conclusions: The phosphodiesterase type 5 inhibitor tadalafil have anti-nociceptive properties and it decreases analgesic effect of morphine, in addition improves tolerance development. These effects probably may occur via NO/cGMP pathway.

      This is analgesia, so is not necessarily relevant for my purposes. Nonetheless, there implies some relevance of cGMP, but the direction isn't yet clear.

    1. Repeated KOR agonist exposure, on the other hand, can result in opposing effects on the dopamine system [27], and desensitization of the KOR [28]

      If they mean what I think they mean, then this implies that chronic KOR is useful. I'll need to check citation 27.

    1. These data suggested that PAT, an indirect-acting KOR agonist, share the common pharmacological property of KOR agonists on morphine tolerance

      PAT is apparently an herbal medicine I should look into. They also imply that KOR agonists act as I expect they do, but I'll need to read the full study to be sure.

      Edit: yup, it appears that chronic KOR agonism is probably a good idea.

      from full text "Utility of KOR agonists is a promising pharmacological tool for attenuating morphine tolerance (Pan, 1998), however, it is difficult to find effective KOR agonists that are devoid of dysphoric and psychotomimetic adverse effects in humans"

      This is the cited study.

    1. The results also showed that diltiazem was able to selectively potentiate the analgesic effect of morphine but not of fentanyl (the reason was not known).

      Fascinating. However, this provides no insight into the subjective effects. However, it does reduce my certainty that any given combination of drugs (sharing these mechanism) will work. There doesn't seem to be consistent results with these L-CCBs plus opioid studies.

    1. The results suggest the euphorigenic and analgesic effects of opioids may be differentiated by using Ca++ channel blockers.

      Yes. That also means that most of the rat studies I've been reading are useless for my purposes.

    1. Results:Nimodipine when administered as a single bolus dose before naloxone administration in morphine-dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period.

      Weird and surprising.This plausibly implies that L-type calcium channel blockers may not be as effective as it first appears.

    1. Nimodipine controlled the escalation of the morphine dose in 9 patients (65%), and placebo in 4 (28%), the difference being statistically significant (P=0.03).

      Consistent with rat data. This is from 1998. I'm sure there's more evidence by now. It's been a while since i researched this, but I think I've previously seen at least one other study.

    1. These results suggest that the elevation of the cyclic AMP levels is involved in the development of morphine withdrawal syndrome and that blockade of the morphine-induced reduction of cyclic AMP levels by chronic rolipram inhibits the development of dependence and the behavioural and biochemical changes induced by naloxone. Furthermore, rolipram may be a useful drug for attenuating the development of morphine dependence.

      Excellent. This implies that theobromine may help prevent opioid tolerance.

  4. May 2020
    1. Results reveal a significant shift in the gut microbiome and metabolome within one day following morphine treatment compared to that observed after placebo. Morphine-induced gut microbial dysbiosis exhibited distinct characteristic signatures, including significant increase in communities associated with pathogenic function, decrease in communities associated with stress tolerance and significant impairment in bile acids and morphine-3-glucuronide/morphine biotransformation in the gut.

      Unsurprisingly, various substances appear to disrupt the microbiome; artificial sweeteners are not unique. Given that I don't worry about opioids, I probably shouldn't worry about sweeteners.

      However, opioids are known for causing constipation. That is to say, they have a clear effect on digestion. Perhaps I should worry about opioids rather than not worry about sweeteners.

  5. Mar 2019
    1. We have previously shown that antinociceptive effects of morphine are enhanced in histamine H1 receptor gene knockout mice.

      H1 antihistamines enhance the opioid high in humans. Hospitals sometimes administer antihistamines in combination with opioids. It's not hard to find people online who are using this combination recreationally.

  6. Jan 2019
    1. Table 1. Analgesic potency of nalorphine compared with morphine for postoperative pain*

      2 mg appears most effective. download PDF here.

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    Annotators

    1. . Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects

      I would not expect doses this small to impact the opioid receptors.

    1. Treatment effects were more pronounced at discharge

      Symptoms in the treatment group continually improved, whereas symptoms in the placebo group plateaued. Thus, I'm interested in seeing a longer treatment period. Projecting from symptom scores, elimination of symptoms would occur in about 10 days.

  7. Nov 2018
    1. Nimodipine controlled the escalation of the morphine dose in 9 patients (65%), and placebo in 4 (28%), the difference being statistically significant (P=0.03). The dose of morphine was reduced from 313±52 to 174±33 mg/day (P<0.001) in the nimodipine group, and from 254±26 to 218±19 mg/day (not significant) in the placebo group.

      Nimodipine reduced morphine dose in already tolerant patients.

    1. The full text describes how ultra-low-dose naloxone and naltrexone enhance opioids at very slim dose margins. A mere two fold difference on naltrexone dose can determine efficacy: 2 micrograms is effective whereas 4 is not. What's more, this optimal dose changes with sex, mouse strain, opioid agonist used, etc.; this making precise dosing challenging. The mechanism suggested is that filamin A has two binding sites, where only 1 has the desired effect.

    1. We measure the binding affinity of NLX or naltrexone to FLNA in cell membranes as 4 picomolar, i.e. approximately 200-fold higher than their binding affinity for MOR

      This sentence appears to indicate equal potency between the two drugs.

    2. Naloxone binding to A7 cells was displaced by naltrexone but not by morphine, indicating a target distinct from opioid receptors and perhaps unique to naloxone and its analogs.

      So, naloxone has a 200 times higher potency at Filamin A compared to opioid receptors, but I need clarification on whether naltrexone achieves similar potency.

  8. Aug 2018
    1. Prazosin had no analgesic effect alone but dose-dependently potentiated morphine analgesia in morphine-naive mice. Another alpha(1)-adrenoceptor antagonist, corynanthine, had similar effects. Prazosin also increased the analgesic potency of the morphine test dose in morphine-tolerant mice. Naloxone-precipitated vertical jumping was not affected, but weight loss was reduced by prazosin. Acutely administered clonidine potentiated morphine analgesia and alleviated opioid withdrawal signs, as expected. We conclude that in addition to the already established involvement of alpha(2)-adrenoceptors in opioid actions, also alpha(1)-adrenoceptors have significant modulatory role in opioid analgesia and withdrawal.

      This is interesting but not exactly surprising, given that both are depressants. What is surprising, however, is the contrast between this and the fact that stimulants also enhance morphine analgesia.

      Potentiation of Opioid Analgesia by Psychostimulant Drugs: A Review00084-0/fulltext)

  9. Dec 2017
    1. If the South Bronx were a state, it would have the second highest rate of drug overdose in the country after West Virginia.

      Wow! Very sad and disturbing.

  10. Nov 2017
    1. His doctor cut off his supply and urged Hale to enter a detox program. That didn’t work. Hale, still in agonizing pain and now suffering from intense withdrawal symptoms, returned to his doctor and pleaded to get back on his opioid regime. The doctor refused.
  11. Oct 2017
    1. Trump blindsides advisers with promised opioid plan Officials are scrambling to produce an emergency declaration by next week.