Wikipedia:Reference desk/Archives/Science/2019 September 16

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September 16

Clinical trials for drug addiction

How came addiction-causing drugs involved in the US opioid epidemic passed clinical trials and were approved by FDA anyway? Were there any shortcomings in determining their addictive properties during trials and considerations of using non-addictive alternatives not based on opioids? Brandmeister^talk 09:55, 16 September 2019 (UTC)

Such trials are carefully controlled, so the patients would be given a set dosage for a set period of time, then the test would end. It's unlikely they would up the dosage and keep them on it indefinitely. They might follow up with the patients a bit after the trial ended, but it often takes years for the most serious consequences of opioid abuse to manifest, likely beyond the term of the follow-up studies. Also, those (ab)users might well drop out of the study follow-up.

On a more sinister note, if the drug companies funding the studies didn't want to find any bad news, they could tweak the study to avoid it (lower dosages, shorter trial periods, less follow-up, exclude those with a history of drug and alcohol use or addictive behavior, no follow-up questions about addiction asked of the patients or open-ended questions like "Are you having any other trouble as a result of taking X" ?). They could also blame the patients, saying "They agreed in the contract they signed not to take any opioids after the trial ended, and they violated this agreement, thus they were excluded from the study results". This is similar to how in the Flint water crisis, the government officials didn't want to find lead in home water samples, so let it run for 10 minutes, to clear most of the lead, prior to taking samples, and would blame the homeowner for having lead pipes, when the lead levels were still too high.

There's a fundamental conflict of interest in having drug companies fund the studies. To eliminate that, we could have an independent commission, ideally of applicants chosen at random, thus free of political influence from those getting hefty campaign contributions from drug companies, which would pick universities to perform the study. They could still use drug-company funding, but in this way the university could set the conditions, and if they found bad results, it would not exclude them from future funding of drug studies from that company. SinisterLefty (talk) 11:21, 16 September 2019 (UTC)

That's what I suspected, because it's strange that opioids (including fentanyl) whose addictive properties have been known before hit the clinical stage and non-opioid alternatives weren't. Seemingly boosting the drug sales due to addictive properties was at play. Brandmeister^talk 11:32, 16 September 2019 (UTC)

FDA published its action plan last year: FDA Opioids Action Plan (2018). They state that scientific evidence regarding long-term use is "lacking," and that the risk-benefit analysis needs to be reassessed.

They also published a special report, A Proactive Response to Prescription Opioid Abuse, which was also published in the New England Journal of Medicine.

Nimur (talk) 14:40, 16 September 2019 (UTC)

It's important to note, anyways, that many of these drugs were on the market long ago. Oxycodone was introduced in 1916 in Germany and 1928 in the U.S. Hydrocodone hit the market in 1923, Fentanyl in 1968. The protocols for testing and bringing to market these various drugs was MUCH different that far in the past. What it would take to bring them to market in the 21st century is likely much different than earlier in the last century. --Jayron32 16:07, 16 September 2019 (UTC)

Also note that a large part of the problem, in the US, is how opiods are prescribed. If they were prescribed for those with terminal cancer, then that would be OK, but prescribing them to large numbers of people with chronic pain is completely inappropriate. Unfortunately, that seems to be exactly what has happened: [1]. SinisterLefty (talk) 16:25, 16 September 2019 (UTC)

A 2007 law gave the FDA considerable more flexibility in how it approves drugs, through a system called Risk Evaluation and Mitigation Strategies. Basically, the FDA is much more able now than 25 years ago to severely limit how a new drug is even prescribed, limit the circumstances under which a patient may be given a refill, and order specific monitoring programs. There are mixed opinions on whether this program can be successful, described here. Though people seem to agree it has not been successful for opioids. Someguy1221 (talk) 00:25, 17 September 2019 (UTC)

• Doing proper clinical trials is very, very, very hard. Failure to do so is not necessarily proof of fraud.

The problem of p-hacking clinical studies (again, not necessarily due to fraud - imagine this comic but with multiple research groups running the various color tests) has led to the US and EU to create clinical trials registries, and force Big Pharma to list every study they make here (more or less). The idea was that a high rate of "disappearing" or inconclusive studies would tell the regulating authorities that the one drug who passed the trials might benefit from a replication study.

This is a fairly recent development (post-2000) compared to the US opioid crisis (per our article it starts in the 1990s); and I would not say all is well today either, but I suppose that the problematic drugs did honestly pass a deficient approval process at the time.

There is of course much to be said on other aspects of the whole affair, such as the gigantic marketing budgets of Big Pharma and the "cool, clients will be back, just don't tell the government" attitude when the first signs of large-scale addiction came up. Tigraan^{Click here to contact me} 13:39, 17 September 2019 (UTC)

As far as I know, addictive potential is not a reason for the FDA to refuse approval of a drug, unless the FDA judges that the risk of addiction is so substantial that it outweighs any possible benefit of the medication, which it rarely does. (If a drug is super-addictive but doesn't do much else, it usually never gets submitted for approval to begin with.) Drugs judged to have addictive potential get placed on the U.S. controlled substances schedule, and then it's up to the DEA to limit abuse and illicit use. Medical practitioners are the ones who decide to prescribe drugs; it's basically up to them to consider "non-addictive alternatives" if warranted. This is why Purdue Pharma encouraged doctors to prescribe more opioids. And the fact is, under the U.S. medical system especially, it's often easier for a doctor to just prescribe some pills rather than try to untangle a difficult health issue. For instance, see this post by a U.S. ob-gyn certified in pain medicine. --47.146.63.87 (talk) 07:20, 19 September 2019 (UTC)

• I keep reading assertions (mostly from patient advocates, I guess) that people who take opioids for pain rarely get addicted, and that the Opioid Crisis happens because the Drug Enforcement Agency, groping for a reason to exist, threatens doctors who prescribe effective doses, and so patients with chronic pain turn in desperation to the black market, where potency is unpredictable. —Tamfang (talk) 22:44, 20 September 2019 (UTC)

• That doesn't sound right to me. The dosage needs to be steadily increased because users develop a tolerance to them, and eventually they get to a dosage that doctors can't legally prescribe, and the patients switch to the black market. Another reason for patients to go black market is that legal drugs just get too expensive. The lesson is that opioids just aren't appropriate for chronic pain, except perhaps in terminal patients. SinisterLefty (talk) 23:16, 20 September 2019 (UTC)

There isn't a legal "maximum dose per prescription" for controlled substances in the U.S., though providers may be hesitant to prescribe very high dosages, and insurers may place restrictions on how large a quantity they'll cover. As our article on the opioid epidemic says, some people have switched from prescribed opioids to illicit heroin because the heroin is cheaper. Also it cites a mix of studies, with one suggesting the majority of opioid abusers started with legally-prescribed opioids while another suggesting most began with illicit usage. --47.146.63.87 (talk) 10:34, 22 September 2019 (UTC)

What's your source for that first sentence? ←Baseball Bugs ^{What's up, Doc?} carrots→ 11:47, 22 September 2019 (UTC)

signs of fissure healing

The following discussion is closed. Please do not modify it. Subsequent comments should be made on the appropriate discussion page. No further edits should be made to this discussion.

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What are the signs and symptoms of anal fissure being healed? Search engines aren't much helpful here. —usernamekiran(talk) 18:01, 16 September 2019 (UTC)

For medical advice, you'll need to speak to your doctor. --Jayron32 18:14, 16 September 2019 (UTC)

@Jayron32: hi. I was asking this generally, out of curiosity. But you are still right. I will discuss this with doctor friend. I will definitely have follow-up questions, and it would be better to have face to face discussion. See you around —usernamekiran(talk) 09:41, 17 September 2019 (UTC)

The discussion above is closed. Please do not modify it. Subsequent comments should be made on the appropriate discussion page. No further edits should be made to this discussion.

Survival instinct in moths and mosquitoes

Why do moths (of the sort mothballs are made for) tend to rest on flat surfaces, fly limply and otherwise lend themselves to easy smacking, whereas mosquitoes, and even large night butterflies (which don't seem to have an obvious reason to fear us) tend to be much wilier and sneakier in their movements and places they choose for resting? 93.136.126.192 (talk) 20:48, 16 September 2019 (UTC)

Since (female) mosquitoes need to drink the blood of animals to reproduce, they are likely to be swatted at (usually with the tail). But other flying insects may rarely encounter larger animals that could swat at them, so don't need a defense strategy. Also, some flying insects seem to be at the end of their life-cycle anyway, having already reproduced, so at that point it doesn't matter if they live or die.

Moths also rely more on camouflage to hide than evasive maneuvers. When they land on the right surface, they can be difficult to spot. But, on the wrong surface, they are quite obvious, at least to us. Predators with lesser vision might miss them, especially when they are still, as many predators rely heavily on motion to detect prey. Also, having big floppy wings makes it difficult for evasive tactics to succeed, as they make too large, visible, and slow of a target, so it's best to just try to hide in plain sight. SinisterLefty (talk) 21:02, 16 September 2019 (UTC)

Clothes moths in their original habitat spend most of their time hidden, don't directly molest other creatures, and have few if any active predators, so they haven't had enough time (clothes being a relatively recent invention) and selection pressure to evolve evasive tactics. By contrast, mosquitoes directly feed on hosts and can cause fairly prompt irritation so that those hosts come to recognise and combat their presence and the mosquitoes in turn have evolved to evade that combat. As for night-flying butterflies and larger moths, they are preyed upon by many species of bats and have therefore evolved strategies to (sometimes) avoid being eaten. {The poster formerly known as 87.81.230.195} 90.202.210.107 (talk) 23:29, 16 September 2019 (UTC)

Yeah, that sounds reasonable. I missed the fact that humans are really the only animal which actively seeks out clothes moths. 93.136.66.74 (talk) 09:37, 17 September 2019 (UTC)