Pain Management Versus Opioid Abuse: Glimmers of Light

Doc Gumshoe follows up on A Troubling Quandary

By Michael Jorrin, "Doc Gumshoe", October 18, 2017

[ed. note: Michael Jorrin, who I dubbed “Doc Gumshoe” years ago, is a longtime medical writer (not a doctor) who writes for us a couple times a month about health issues and trends.  He does not typically focus on specific investment opportunities, but has agreed to our trading restrictions… as with all of our authors, he chooses his own topics and his words and opinions are his alone]

At the end of the first installment on this subject I promised to lift the curtain on some glimmers of light that have emerged in this troubling picture.   Before getting up to launch velocity, I need to do a bit of review.

First, we need to understand one simple, basic, underlying truth: in most cases, our pain response is an essential survival signal.   The sensation of pain tells us that something is amiss and needs to be remedied.   This is true of both the fast type of pain, which is a response to mechanical or thermal events (bangs, cuts, burns, etc), or the slow type of pain, which is a response to something wrong systemically, whether something relatively trivial like indigestion, or any of a huge and intimidating range of non-trivial conditions and diseases.   Those two general types of pain are transmitted by different nervous systems.   Fast pain impulses get to the brain in less than one tenth of a second after the incident, while slow pain impulses begin to trickle into the brain several seconds after the chemical agents reach the nerve endings, and then increase over longer periods, sometimes as long as hours.

The most immediately useful response to pain is to determine the cause and try to deal with it.   This is generally fairly simple with fast pain.   If you burn yourself picking up the cast-iron skillet without a pot-holder, you can run cold water on your hand and then put on some lotion; systemic pain medication is usually unnecessary.   But if you develop a severe pain in your lower back, and it gets worse overnight and doesn’t go away, you might need to consult a health professional to try to find the cause.   And if, despite the interventions of the health professional and short-term pain medications, the pain persists, you might find yourself in the situation I described in the previous installment.

That situation embodies some inherent conflicts.   As noted in the previous Doc Gumshoe sermon, chronic pain affects close to one third of the US population, and the most effective drug treatments for pain are agents that address the μ opioid receptor, but opioid abuse is endemic here in the USA, and opioid overdoses kill about 175 of us every day.

Lots of different cohorts contribute to this situation in many different ways.   People in pain increase their opioid doses in an attempt to cope with their lives, perhaps unknowingly flirting with addiction, while others knowingly risk addiction in the search for pleasure and a good time.   The economics of the health-care system may make it easier to treat pain with cheap opioids than with some relatively more expensive alternatives that may be less addictive.   And shady characters in quest of easy money provide people with those more addictive drugs.

The pharmaceutical outfits that make and market opioids attempt to dissuade users from becoming addicted to their products mostly through formulation – either by compounding the opioid with one or more other substances that are intended to minimize addiction, or by making slow-release tablets that deny users the immediate rush of pleasure that rewards addicts.   For example, oxycodone, which by itself is an immediate-release agent, is available in seven different formulations intended to deter addiction while perhaps augmenting the basic pain-relieving activity of the opioid itself by adding other analgesics.   In theory, bringing down pain levels by multiple mechanisms would reduce reliance on the opioid channel and thus perhaps lower the odds that the patient would take another opioid pill when the pain level increased.

The formulation strategy is very limited in its effectiveness.   Addicts quickly learn how to crush or dissolve their pain pills and take them in such a way as to get that quick rush that they crave.   And, paradoxically, putting other agents in the mix can add risks.   Both oxycodone and hydrocodone are available in forms compounded with acetaminophen (Tylenol).   Taken regularly over long periods, both the oxycodone-acetaminophen pill (Percocet) and the hydrocodone-acetaminophen pill (Vicodin), will likely elevate liver enzymes and can cause significant liver damage, especially when taken with alcohol.   And large doses of those drugs, in the amounts favored by addicts to provide that immediate rush, are thought by some to be a leading cause of liver failure, leading to liver transplants, and in some cases, death.   There are formulations consisting of 5 mg. of oxycodone compounded with 325 mg. of acetaminophen.   A dozen of those would put a person at 3900 mg. of acetaminophen, which is right up against the 4000 mg. danger marker, while only yielding 60 mg. of the opioid – nowhere near enough for an addict to get a rush.   So, sometimes it’s not the opioid that kills the addict, but that supposedly benign little pain killer that we give our kids.

So, is there a way to deliver the pain relief that opioids can provide without also increasing the risk of addiction?

Maybe less is more…

A small pharmaceutical company has developed a drug that – perhaps! – accomplishes just that.   The company is Nektar Therapeutics (NKTR) in San Francisco, and the drug in question is NKTR-181, unnamed as of this writing.   (Before I go on about this drug, let me state plainly that I have no expertise whatever in assessing the economic potential of Nektar, other than to say that it is a quite small company, and that if their pain medication scores a hit, the company itself could do well.   But I have not bought any shares and do not plan to for the foreseeable future.)

At first glance, NKTR-181 would seem to be a total bust.   It is about an order of magnitude less potent than opioids like oxycodone and hydromorphone, and it is afflicted with many of the common side effects that come with other opioids.   It is inherently very slow-acting due to its molecular structure, and therefore unsuitable for the treatment of acute pain.   So why is it viewed as a promising drug?

Exactly for some of those reasons.

How quickly a drug begins to deliver pain relief depends on the speed with which it reaches the pain centers in the brain.   These centers – the analgesia systems of the brain and spinal cords – are highly complex, and also highly sensitive to opioids.   About half a century ago it was discovered that really miniscule quantities of morphine, injected directly into certain areas of the brain, result in an extreme degree of analgesia – a nearly total suppression of pain impulses.   As research into this matter has continued, a number of naturally-occurring opiate-like substances have been discovered in the nervous system, and many areas of the brain have opioid receptors.   Opioids are indeed our natural, built-in pain suppressors.

The fast-acting opioids that are commonly used for pain management reach those opioid receptors in the brain pretty quickly – in the case of oxycodone, it can take as little as fifteen minutes for the drug to enter the system, get absorbed in the blood stream, travel to the pain centers in the brain, and elicit a response.   That depends on the dose, of course – the drug trickles in over time, and with a larger dose, the amount required to elicit a significant response gets to the target receptors that much sooner.

That’s where NKTR-181 has this entirely counterintuitive advantage.   Where it takes oxycodone a quarter of an hour to start delivering results, NKTR-181 can take as long as eight hours.   That’s because the molecule itself is very slow to be absorbed into the circulation – sometimes as long as four hours – and then, very slow to cross the blood-brain barrier – again, perhaps four hours.

So there’s no way for the would-be drug abuser to get a rush by taking NKTR-181.   And the slow onset of the opioid effect is not due to any formulation, but to the inherent structure of the molecule.   Therefore, it is extremely unlikely that tampering with the drug itself would increase the potential for abuse.

The low potency of NKTR-181 is also, in a sense, an obstacle to abuse.   Whereas for certain chronic pain patients, 40 mg of oxycodone per day would be a dose adequate to keep their pain levels under control, the amount of NKTR-181 needed to attain the same level of analgesia would likely be about ten times that amount -400 mg per day.   But 40 mg of oxycodone in a 24-hour period is nowhere near enough to provide the same gratifying effects that addicts crave, nor would the equivalent amount of NKTR-181.   And the higher the dose, the greater likelihood of encountering the kind of side effects that are not dangerous, but definitely disagreeable – nausea, vomiting, and so forth.   So, even if patients boost their dose, there’s no immediate rush and they could feel lousy for a few hours.

A clinical study comparing NKTR-181 with oxycodone and placebo used the Drug Liking Visual Analog Scale and found that at all dose levels, NKTR-181 had significantly (P < 0.0001) lower Drug Liking scores than oxycodone, and about the same scores as placebo (Webster L, Pain Medicine  03/10/2017).    At the 2017 PAINWeek conference in Las Vegas in September, Nektar presented results from its SUMMIT-07 trial, which reported that more than 98% of patients taking NKTR-181 experienced no withdrawal symptoms whatsoever, either during the trial, or after discontinuing the drug at the conclusion of the trial.