As a Pharmacist in a primary care clinic with a family medicine residency program that is run out of our clinic, we get several drug information questions on a daily basis. Recently we received several inquiries about opioid-induced constipation and the drugs that treat it.

Patients were coming in asking for medications they had seen on TV commercials and the Residents wanted to know if there is a difference, is anyone drug better than others.

Opioids remain the most commonly used major pain-relieving medications for chronic noncancer pain.  Opioids are associated with several unwanted side effects, including feeling sleepy, respiratory depression, tolerance, nausea, vomiting, abdominal pain, and constipation. Unlike other gastrointestinal (GI) side effects constipation doesn’t get better and can interfere with pain treatment.

OIC is caused by the activation of receptors, which leads to reduced gastric, biliary, pancreatic, and intestinal secretions, increased absorption of water from bowel contents, and decreased gastric motility.

World Health Organization (WHO) guidelines for the treatment of cancer-related pain call for immediate oral administration of drugs beginning with non-opioids then move onto mild opioids such as codeine then “strong opioids such as morphine until the patient is free of pain.

To maintain patients free from pain, drugs should be given around the clock, every 3-6 hours”. The WHO notes that this approach, which focuses on administering the right drug at the right dose at the right time, is inexpensive and 80%-90% effective. Although initially developed to relieve cancer pain, the WHO “ladder of pain” has since been validated for other types of chronic pain.

Current guideline recommends daily ingestion of 25 to 30 g of dietary soluble fiber; adequate fluid ingestion (1.5-2 L daily); regular aerobic exercise (adjusted to individual physical fitness and preferences); balanced diet; regular meal pattern; and avoidance of heavy meals, fat, insoluble fiber, and flatulent foods.

Although these measures should be recommended to all patients during opioid initiation, it is unlikely that dietary and lifestyle changes alone will prevent or treat OIC.

^{OTC medications}

• Osmotic agents (e.g., lactulose [Rx in the U.S.], PEG 3350 [Miralax-U.S., RestoraLAX-Canada, others], sorbitol, and saline laxatives [see below]) promotes the secretion of water into the lumen of the colon and stimulate the movement of the bowel. The main side effect is diarrhea. Onset is typically from 12 to 96 hours. Glycerin suppository onset is usually within 15 to 60 minutes.
• Fiber/Bulk agents (e.g., methylcellulose-U.S. only [Citrucel, etc], calcium polycarbophil [FiberCon-U.S., Prodiem Fibre Therapy-Canada, etc], psyllium [Metamucil, etc]) hold water in the stool, increase stool weight, increase colonic distension, and improve the frequency of bowel movements. The main side effects are bloating and cramping. Onset is typically from 12 to 72 hours.
• Stimulant laxatives (e.g., bisacodyl [Dulcolax, etc], sennoside [Senokot, etc]) increase intestinal motility and colonic secretions. The usual onset with oral formulations is six to ten hours, possibly up to 24 hours. The onset with rectal suppositories is 15 to 60 minutes. The main side effect is cramping.
• Stool softeners (e.g., docusate [Colace, etc]) improve the interaction of water and solid stool.
• Saline laxatives, (a type of osmotic laxative; e.g., magnesium hydroxide, magnesium citrate, oral sodium phosphate liquid) draw water into intestines and colon by osmosis to increase motility. Major side effects are cramping dehydration and electrolyte disturbances.  Onset is 30 minutes to six hours (magnesium hydroxide) and 30 minutes to three hours (magnesium citrate, oral sodium phosphate). The onset of sodium phosphate enema (Fleet, etc) is usually within one to five minutes.

These products are available OTC and are appropriate to use in OIC therapy. The most common regimens involve the combination of a stimulant laxative, such as bisacodyl or senna, and a stool softener.

There are three types of stool softeners: surfactants, lubricants, and osmotic.

Surfactants such as docusate sodium are emulsifiers that facilitate the admixture of fat and water in the feces.

Lubricants such as mineral oil delay absorption of water from stools in the colon, thus softening the feces.

Osmotics draw water into the colon to hydrate the stools.  Bulk-forming laxatives such as psyllium should be avoided because they increase stool bulk and distend the colon, which can worsen abdominal pain and bowel obstruction when opioids prevent movement that pushes contents out of the canal.

^{Prescription medications}

When the combination of diet, lifestyle, and OTC laxatives and stool softeners are insufficient to relieve OIC, most clinicians and patients turn to prescription medications.

Rx Therapy	Cost*	Indication (Adults Only)	Therapeutic Considerations
Linaclotide (Linzess [U.S.]; Constella [Canada])	~$12/day (U.S.) ~$4 to $6/day (Canada)	Chronic idiopathic constipation IBS with constipation	Do not crush or chew; can sprinkle contents on applesauce or water (can give via nasogastric tube) Give on an empty stomach, 30 minutes before first meal of the day Minimal absorption, interactions unlikely Expect improvement in week 1 for bowel symptoms; longer onset for abdominal symptoms. Keep this in mind if treatment delayed (e.g., during transitions of care). No adjustments needed for renal or hepatic impairment Protect from moisture; keep in original container with supplied desiccant
Lubiprostone (Amitiza-U.S. only)	~$12/day	Chronic idiopathic constipation IBS (women) with constipation Opioid-induced constipation in patients with chronic non-cancer pain	Swallow whole, do not break or chew No known drug interactions Reduce dose for moderate and severe hepatic impairment May not be effective in patients taking methadone. In vitro and preliminary data26 suggest methadone may interfere with lubiprostone’s activation of GI chloride channels.
Methylnaltrexone (Relistor)	~$55/day (oral; U.S.) $109/12 mg (injectable, U.S.) ~$40/12 mg (injectable, Canada; oral not available in Canada)	Opioid-induced constipation in patients with chronic non-cancer pain (U.S.) or with advanced illness, receiving palliative care	No known drug interactions Reduce dose for moderate and severe hepatic impairment Reduce oral (U.S.) and injectable dose for renal impairment Adjust dose for under- or overweight Stop other laxatives; can restart if needed after 3 days (U.S.) May see less response in those on opioids for less than 4 weeks Monitor for opioid withdrawal Oral Give on an empty stomach, at least 30 minutes prior to the first meal Subcutaneous Injection Works within 4 hours of injection in up to 50% of patients (median 24 minutes); advise patients to stay close to the toilet Give injection while seated or lying down Protect from light Consider stopping if no response after 4 doses (Canada)
Naldemedine (Symproic-U.S. only)	~$11/day	Opioid-induced constipation in patients with chronic non-cancer pain	Take with or without food Avoid with strong CYP3A inducers and other opioid antagonists; monitor with moderate and strong CYP3A4 inhibitors and P-GP inhibitors Avoid with severe hepatic impairment May see less response in those on opioids for less than 4 weeks Monitor for opioid withdrawal
Naloxegol (Movantik)	~$11/day (U.S.) ~$7/day (Canada)	Opioid-induced constipation in patients with chronic non-cancer pain	Can crush tablet; mix the powder with water for oral or nasogastric tube use Give on an empty stomach, 1 hour prior to a first meal or 2 hours after Contraindicated with strong CYP3A4 inhibitors; avoid with moderate inhibitors (if possible) and grapefruit juice Reduce dose for moderate to severe renal impairment, with weak CYP3A4 inhibitors (Canada), with moderate CYP3A4 inhibitors (if users can’t be avoided), or if not tolerated Avoid with severe hepatic impairment May see less response in those on opioids for less than 4 weeks Stop other laxative therapy; may restart in 3 days if needed Monitor for opioid withdrawal
Plecanatide (Trulance-U.S. only)	~$12/day	Chronic idiopathic constipation	Swallow whole; can crush in applesauce or water (can give via nasogastric tube) Give with or without food Negligible absorption; no expected drug interactions Protect from moisture; keep in the original bottle with desiccant

* Medication pricing by Elsevier, accessed November 2017 (for U.S. pricing). The cost listed is the wholesale acquisition cost (WAC) in the U.S. and Canada.

There is little published clinical evidence of the efficacy of complementary and alternative therapies in OIC or, in fact, any type of constipation. The greatest body of evidence attests to the benefits of hypnotherapy and relaxation techniques in patients with IBS. However, since IBS is strongly related to stress, it is doubtful that these approaches would have much effect on OIC, which, as noted earlier, primarily results from the specific mechanism of action of opioids.

Wenk et al evaluated the effects of baker’s yeast in an open-label study involving cancer patients upon opioid initiation, of whom were already constipated. Patients received an initial dose of 6g, doubled daily until laxation occurred. Eleven patients had bowel movements with no additional laxatives required. The authors hypothesize that brewer’s yeast triggers a fermentation process in the intestine leading to water absorption in the lumen.

Opioid-induced constipation significantly affects patients’ quality of life. Quite often, the effect is so debilitating that patients stop taking or refuse to take their medication. In effect, this means they choose pain over constipation.

When Bell et al surveyed 611 patients with non-cancer chronic pain who took opioids 2 or more days a week as well as laxatives, 81% reported constipation as a side effect of opioids and nearly all said it affected their quality of life. More than half said the effect on their quality of life was “moderate-to-great or great.” The condition also affected their activities of daily living.

To relieve their constipation, one-third reduced the dosage, skipped dosages, or stopped using their medication altogether. Of those who reduced their opioid dose or stopped taking their medication, 92% reported increased pain as a result, pain so severe it impacted their quality of life.

Opioid-induced constipation and bowel dysfunction affect up to 90% of patients who receive opioid therapy for chronic pain. Prophylactic bowel management combined with lifestyle approaches such as hydration, exercise, and regular toileting efforts may prevent OIC or reduce its severity.

If OIC occurs, stimulant laxatives combined with stool softener should be the first-line treatment. In patients who do not respond, an osmotic laxative may be added. Laxative-refractory patients may require a different opioid and/or the addition of lubiprostone or a peripherally acting opioid antagonist

Approximately half of American adults take a vitamin or mineral supplements. There’s so much hype about dietary supplements now days, and very often the benefits are not there. Asking your Health Care Providers (Doctor, Nutritionist) to help you figure out which vitamins will be best for you is the best policy.

A new study published in JAMA concluded It is always better to get vitamins and minerals from the diet, from foods. However, a small percentage of the population may benefit from vitamins such as pregnant women, infants, or older adults either because they have a medical condition that could interfere with absorption or metabolism of a vitamin or mineral, or are taking medications that may have that adverse effect.

Dr. Manson’s take away points:

1.    Healthy food is better than pills.

2.    For certain people there’s enough evidence to support taking vitamins and minerals, but for the generally healthy population with good diets, there is no evidence.

The overview was based on several professional society guidelines, and from randomized clinical trials. Dr. Manson also reported that they’ve done many of the trials themselves, testing the role of higher doses of some of these vitamins and minerals — vitamin C, vitamin E, beta-carotene, folic acid. They’re testing vitamin D and Omega-3s now, as well as multi-vitamins.

For healthy general population, there is no additional benefit from supplementation. And there are advantages of getting the vitamins and minerals from foods because they’re better absorbed that way.

For the population who can benefit from vitamins and supplements are as follow:

·         Pregnancy: folic acid, prenatal vitamins

·         Infants and children: for breastfed infants, vitamin D until weaning, and iron from age 4-6 months

·         Midlife and older adults: Some may benefit from supplemental vitamin B12, vitamin D and/or calcium

·         Other high-risk groups: Medical conditions that interfere with nutrient absorption or metabolism, osteoporosis, selected medication use, and others.

Then why is it that so many doctors routinely recommend multivitamins even to healthy younger folks?

There is one large-scale randomized trial that suggests there may be a modest reduction in the risk of cancer, and we are trying to see if those findings can be replicated. Dr. Manson is doing a large randomized trial of multivitamins right now, a second trial, looking at the effects in reducing risk of cancer and cardiovascular disease.  There is no clear evidence that people who have a healthy, well-balanced diet will get benefits from multivitamins or other dietary supplements.

It’s important to know that you’re taking a high-quality supplement in terms of getting the amount of vitamin or mineral that it says it has on the label and also that there isn’t contamination by microbes, heavy metals or toxins. One way to ensure that you’re getting a product that has undergone independent quality control testing and independent audit is to look for labels such as U.S. Pharmacopeia, NSF International or UL, or other information on the label suggesting it’s undergone an independent quality control test.

Generally, patients are overwhelmed by all of the promotions of vitamins and minerals and other dietary supplements. Some of the individual supplements are more than 10 times the recommended amount. The single supplements that people most often take in high doses that we should be most concerned about are vitamin E and beta carotene, which have been linked to some risks when taken in very high doses.  In order to avoid risks and get the recommended amounts if vitamins and minerals the best thing you can do is to have well balanced diet.