Overview and Novel Therapies for Opioid-induced Constipation

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Recently Drs. C. Kominek and J. Fudin (pharmacists) teamed up with their medical colleagues Drs. J Gudin and A. Laitman to write a review for Practical Pain Management on novel and emerging therapies for the treatment of opioid-induced constipation, including the newest class known as PAMORAs.  Dr. Kominek was kind enough to prepare a short blog review on the topic to move our blog followers.  Although this piece is short, it’s quite impactful, so pull up a stool and enjoy her summary.

Dr. Kominek had this to say…

Opioids function by interacting with opioid receptors located throughout the central and peripheral nervous systems. There are multiple types of opioid receptors that exist including mu, kappa, and delta receptors. Activation of mu-opioid receptors is primarily responsible for the analgesic effects of opioids, but also contributes to euphoria, tolerance, dependence, and respiratory depression. Because mu-opioid receptors are also located within the gastrointestinal tract they contribute to opioid-induced constipation. Kappa-opioid and delta-opioid receptors are associated with analgesia, but to a lesser extent. Additionally, certain kappa- receptor subtypes may enhance sedation, myosis, and dysphoria while delta- receptors may also affect the endocrine function and respiration.

Most commonly, opioids operate as opioid-receptor agonists. Examples of opioid agonists include morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, methadone, heroin (diacetyl-morphine).  The ceiling dose with careful titration and slow escalation over time, is theoretically limited only by side effects, or development of hyperalgesia.  Mixed agonist/antagonists are also available, such as pentazocine and butorphanol, which activate some receptors while antagonizing others. This class does have an analgesic ceiling effect and my lead to withdrawal symptoms. Buprenorphine, a partial agonist/antagonist, and like the mixed agonists/antagonists has an analgesic ceiling effect. Opioid receptor antagonists such as naloxone are employed in opioid overdose situations to reverse respiratory depression. Interestingly, Purdue Pharma recently released Targiniq ER which is a combination product containing oxycodone and naloxone together in an extended release formulation – while little mention has been made of it, intuitively this product would result in less constipation, as a continuous release formulation of naloxone should block opioid receptors in the gut.  In fact, a “prolonged release” formulation of naloxone is currently in clinical trials.

Peripherally acting mu-opioid receptor antagonists (PAMORAs) are a relatively new class of medications that work to block opioid effects on the GI tract that lead to constipation. The first medication in this class of medication was almivopan; however, this medication was not labeled for the management of opioid-induced constipation but for speeding gastrointestinal (GI) recovery following certain types of bowel surgery. Some data has shown that the use of almivopan increased the risk for myocardial infarction. The next PAMORA on the market was methylnaltrexone. Initially, this medication was only indicated for use in palliative care patients experiencing constipation not relieved by laxative therapy. One downside of this medication is that it requires subcutaneously administration and dosing is dependent on indication as well as weight. Recently, the Food and Drug Administration (FDA) approved naloxegol, an oral PAMORA, for opioid-induced constipation in patients with chronic non-cancer pain. For more information on opioid-induced constipation and PAMORA, see Combating Opioid-Induced Constipation: New and Emerging Therapies [Gudin J, Laitman A, Fudin J, Kominek C. Practical Pain Management. 2014 Nov/Dec; 14(10):41-48].
(For PDF version, contact Dr. Jeffrey Fudin)

As always, comments are welcome!

CourtneyCourtney Kominek, PharmD, BCPS, completed her Doctor of Pharmacy at the University of Pittsburgh, School of Pharmacy. She completed a PGY-1 Pharmacy Practice Residency at the Dayton Veterans Affairs Medical Center in Dayton, OH, and a PGY-2 Pain Management and Palliative Care Pharmacy Residency at the West Palm Beach Veterans Affairs Medical Center in West Palm Beach, FL. Currently, Dr. Kominek is a Clinical Pharmacy Specialist in Pain Management at the Harry S. Truman Memorial Veterans’ Hospital in Columbia, Missouri.

 

10 thoughts on “Overview and Novel Therapies for Opioid-induced Constipation

  1. I HAVE A SIMPLE TREATMENT – IT WORKS FOR THE WORST!

    I am on the grand daddy of pain medications; Diludid, with XR Tramadol, Baclofen and Lyrica and nightly Serequel and Lidoderm Patches for failed back syndrome after bla, bla bla surgeries – some 30 years in the making. Talk about a recipe for a tough poop chute – some humor. I am The Aberdeen Proving Grounds, so toss your science papers and give this a whirl first.

    These three things WORK and all three are needed: Spectrum Brand Flaxseed, 14 grams first in the morning with two teaspoons of Psyllium Husks in a stirred glass with water. Do the same thing at night before dinner. I use a Mirilax generic (its all the same) with a half a cap full typically at night. This all can be stirred with the flax seed and psyllium husks and taken at the same time.

    The results are the physically longest easy to pass logs you will ever have had in your life. It is also colon healthy. The half dose of the Mirilax keeps a water balance in the bowel. Too much Mirilax and you get unhealthy toothpaste consistency bowel. You want that perfect movement with bulk.

    You need to work up your tolerance to Psyllium Husks so start with one teaspoon for the first three weeks. If you get cramps, just drink warm water and they stop quickly. The cramps go away once you are use to it and your colon will dance with delight (in a nice way).

    The 14 grams of flax seed is the daily allowance. You may choose 7 grams in the morning and 7 at night.

    Health is not about fighting. Its about maintaining. Once a person dedicates themselves to that honesty, they live better lives. It has to be every day, not some silly trend or fad.

  2. I am currently supposed to be taking 4 10mg Norco daily, I have been given 100mg Tramadol ER to take one only at bedtime to keep the pain from waking me up. I almost always run out of my Norco 4-7 days early due to having to take 5 or even 6 a day to make it through my daily activities. Just like “Spyz” comment above, at 5-6 daily, I have NO constipation, I cook nice nutritious meals, and always drink lots of water (3 liters) a day. The last time I ran out of Norco, I took the tramadol 3 times a day and got very bad constipation. Tramadol is really kind of a half-assed pain killer to begin with, then to suffer constipation and headaches in addition to inadequate pain relief makes NO sense whatsoever to me. Especially when 6 Norco would do the job and allow me to actually have an almost normal life!

  3. AAAARGH, the dreaded constipation! We all know by now that constipation is to be expected by the novice and opiophile alike. But is it really? I had the unfortunate serendipity of taking phenytoin concommitedly with oxycodone. My dose was 4 30mg not to exceed 4 each day of the oxy. Taken with the phenytoin created a hyper metabolism and me taking 15-20 of the 30 mgs each day just to fight withdrawal. Yes 450-600mgs of oxycodone and no adverse effects. None. Nada. Zilch. My pain level dropped to 0, and at one point I even forgot there was anything wrong with me and wondered why I was on pain meds. As for the constipation? None. Nada. Zilch. I had at least one healthy bowel movement a day, usually two. I was feeling no pain so I cooked nice home cooked meals regularly and ate healthy. I was hydrated well havig no problem downing the required amounts of water…unlike when taking the prescribed dose of 4 per day and having no appetite, stuck in bed, no activities, no cooking…no wonder we are constipated! But we dont have to stay that way. People please! When you go to your doctor you know you will be labeled a druggy if you complain about dosing….draw up a petition and while waiting to be seen, get signatures of other patients while there. Doctors have got to stop this madness! Not only do we want our lives back, being regular would be an added welcome!

  4. Around 9 pm I reach in a bag of pitted prunes and stuff them in the side of my mouth like chewing tobacco . I wait for the conglomeration to get soft then chew and swallow slowly a little at a time.
    I promise you constipation will not be a problem if you use prunes like chewing tobacco once a day ,your body will get use this and its Bombs Away , the next day.

  5. I thought the DEA Schedules were supposed to be an index of the abuse & harm potential of any particular controlled substance. In my new copy of “Medical Economics”, the ad for Movantik says it has NO abuse potential, NO potential for dependency.
    Why on earth is it Schedule 2, then? Is there some hidden potential for respiratory depression that has not been mentioned?

    1. Carol,
      You are correct. In fact Astra Zeneca who makes the product has submitted a request to reverse the scheduling, and to my knowledge it looks favorable. See the appropriate section in the PPM article that is linked in the post or see the PDF version HERE.

  6. I was moved by this article!

    (Sorry, I couldn’t resist)

    Actually, opioid induced constipation is one of the most bothersome, and sometimes dangerous, side-effects of medicinal pain therapy. However, it is too often an after-thought.

    As a pain specialist, I always want to help my patients with such side-effects. My hope is that physicians ask and that patients are comfortable talking about it.

    1. Dear Dr.Murphy, I have been taking opiod pain meds for a very long time, also i must take sleep meds and anxiety meds, all of which slow down the poo…and I won’t give the lengthy explanation, but having severe constipation can make you feel, well crappy lol, seriously people dont realize how terrible it can be and how it makes you feel, I have tried the increased fluids, exlax, docusate sodium, suppositories, senna, lactulose and some in combo… Either didn’t work or only worked for a while… then the miracle of PEG(Polyethylene Glycol 3350)….it is over the counter and the only side effect was mild nausea, but being 5’6 and 120 lbs, i thought possibly i could cut back on the dosage and it still worked with no nausea…i take it for 4 days on 2-3 days off and i am like a normal person… No cramps, no gas, no messy, no worry if it will work, no racing to the bathroom, it draws water into your bowels thus softening and stimulating bowel movements… Be sure to keep up fluids to not get dehydrated, you can be totally backed up (shows on xrays) and after the 4 th day i thought, its not gonna work…. But it DID, made from a type of sugar that doesnt mess with blood sugar levels… I realize it might not be for everyone but it is worth trying… And it requires no prescription comes in generic versions…i just wanted to see if maybe this could work for your patients…Thank you for recognizing this problem and helping them come up with solutions….

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