It is estimated that anywhere from 25% to 45% of the adult population suffers from long-term pain, which results in a poor quality of life, loss of productive time, and the constant need to take some pain medication (AAPM, 2017). The indirect costs of managing this patient population are enormous due to repeated visits to the emergency room, recurrent admissions and undergoing a variety of costly pain relieving treatments/procedures. One of the most common types of drugs used to treat moderate to severe pain due to non-cancer and cancer causes are the opioids. Over the past 3 decades, the use of opioids has increased dramatically, and it is estimated that about 2% to 3% of the US adult population is actively on an opioid for chronic non-cancer pain. Each year, nearly 250 million prescriptions of opioids are written by healthcare workers (CDC, 2017).
Over the past 2 decades, healthcare workers have also been liberally prescribing opioids for the management of pain and this extensive exposure to opioids has also resulted in the development of a wide range of adverse effects of narcotics. Some of the common side effects of the opioids include the following:
These side effects are well known to healthcare workers. However, one lesser known side effect of opioids is the narcotic bowel syndrome (NBS). The most common opioid-associated gastrointestinal complication is opioid-induced constipation, which presents with nausea, vomiting, abdominal cramps, bloating, and constipation. NBS, on the other hand, is characterized by frequent or long-standing abdominal pain that is associated with long-term opioid use. The pain is often worsened by increasing doses of opioids or with longer duration of use of these agents.
The exact reason why NBS develops is not fully understood, but hyperalgesia is seen in about 6% of patients who are taking opioids chronically. The syndrome can profoundly affect the quality of life and often necessitate multiple visits to the emergency room and hospital admissions. NBS is managed by gradually withdrawing the opioid, and at the same time, preventing the withdrawal symptoms and pain with the use of antidepressants, clonidine, and benzodiazepines. In addition, many patients require laxatives and newer peripheral opioid antagonists to treat constipation. All patients benefit from psychosocial therapy at the same time to prevent relapse.
Narcotic bowel syndrome can easily be confused with several other disorders of the gastrointestinal tract.
Some of the key features about NBS is the difficulty in making the diagnosis, the real possibility of treating the pain inappropriately and its impact on the quality of life. Inappropriate therapy may include increasing the dose of the opioid for pain relief, referring the patient for invasive diagnostic procedures or consulting with a surgeon to rule out mesenteric ischemia. However, the majority of these patients are inappropriately treated with proton pump inhibitors, laxatives, and dietary manipulations.
NBS is not a new entity, and it has been reported in the literature for several decades. However, despite these reports, most healthcare workers appear to be unfamiliar with the diagnosis and have often overlooked it. The exact incidence of NBS is not known, but from the case reports, it is estimated that about 4% to 6% of the population that use long-term opioids develops the syndrome. Based on self-reported questionnaires, it is estimated that about 150,000 individuals in the United States may have NBS; however, these numbers are underestimated because there is no way to confirm the diagnosis. Other recent studies from the gastrointestinal (GI) clinics suggest that in patients with chronic noncancer pain the incidence may be much higher with a longer duration of usage.
It is now estimated that among chronic opioid users 1 out of 20 patient will develop NBS. Thus all healthcare workers who prescribe, dispense or look after patients on opioid must be fully aware of this syndrome so that they may take appropriate and timely action.
While there are no specific populations which are more susceptible to NBS, small studies reveal that NBS appears to be more common in the following sub-populations:
Almost every article on NBS reveals that psychiatric comorbidity worsens NBS and hence once the diagnosis of NBS is made, these patients should be thoroughly evaluated by a mental health professional.
Researchers and healthcare professionals do not know a lot about the molecular mechanisms that lead to NBS. All the existing theories propose that there is activation of the central pain pathways, but how and why this happens is not well understood.
All the previous theories suggest that there is hyperalgesia. Either there is excess stimulation of the peripheral pain nerves, or there is an enhanced response by the central nervous system (CNS) to the pain stimuli. The latest theory suggests that perhaps opioid-induced hyperalgesia may have a neural-immune component. It is believed that there is activation of the immune cells, astrocytes, and microglia in the CNS, which then results in modulation of pain through the release of various proinflammatory chemokines and cytokines. The cascade of events that follow leads to a circular pattern of neuronal excitability that eventually is associated with an enhanced perception of pain.
The activation of the glial cells is believed to occur in the dorsal horn of the spinal cord, and these cells most likely mediate the hyperalgesia of NBS via several mechanisms. Firstly, these activated glial cells could be releasing central excitatory neurotransmitters like prostaglandins, nitric oxide, growth factors and excitatory amino acids. Secondly, the glia may also be releasing mediators that enhance the release of pain neurotransmitters from sensory nerves. Thirdly the glia may be activated by the pain neurotransmitters like substance P, glutamate or ATP, which in turn reinforce their nociceptive responses, thus creating a positive feedback loop. Fourthly, glial cells are activated by fractalkine (CX3CL1), a microglial agent which may further enhance the pain sensation.
Other theories suggest that the nerve cells in the gastrointestinal tract develop opioid tolerance. No one theory can completely explain all the feature of NBS, but experts on pain believe that the pathophysiological is probably more complex and involve many more pathways.
The recent discovery of excitatory and inhibitory G-coupled opioid receptors may shed more light on the molecular mechanisms of NBS. It is established that the inhibitor G-coupled receptors are known to produce analgesia, and the excitatory G-coupled receptors produce anti-analgesia. Since many people develop tolerance to opioid analgesia with time, the anti-analgesic effects of these excitatory receptors may be responsible for causing hyperalgesia.
Another theory for NBS suggests that the development of hyperalgesia may be associated with the activity of cholecystokinin (CCK) and/or dynorphin in the rostral ventromedial medulla. The CCK is said to trigger a sequence of biochemical events that lead to neuroplastic changes in the spinal cord and CNS; this plasticity facilitates the increased release of excitatory pain neurotransmitters, resulting in hyperalgesia.
All the present theories only partially explain the association between use of opioids and hyperalgesia, but why some people do not develop NBS is not well understood.
In NBS, it is the paradoxical abdominal pain with opioid use that is often unrecognized, and hence, the condition often goes unrecognized, resulting in escalating use of opioids, which in turn causes more severe abdominal pain. The key feature of NBS is the worsening abdominal pain that is centrally mediated. It should be differentiated from the usual peripheral adverse effects of opioids like nausea, vomiting, bloating, abdominal cramps and constipation.The latter collection of symptoms may occur in conjunction with NBS.
The diagnosis of NBS is clinical. No laboratory or imaging test can help with the diagnosis. The diagnosis of NBS is often missed because of the lack of awareness of its existence. To make the diagnosis one has to make an association between long-term opioid use and the worsening abdominal pain. 
The following features should be present to help make a diagnosis:
The abdominal pain may come on with a varying dosage
In most patients with NBS, the diagnosis is often delayed because of the lack of specific features and unawareness.
Laboratory workup includes the white cell count which is usually normal in people with NBS.
While imaging is not required to make the diagnosis of NBS, abdominal x-rays are often done to rule out other pathologies like bowel obstruction, perforated viscus or renal calculi. In patients with NBS, one may note the presence of partial bowel obstruction or ileus. Fecal impaction may be seen in many patients as a result of opioid-induced constipation.
Before embarking on any treatment, it is important to appreciate that NBS is a hyperalgesic syndrome caused by opioids. Any negative interaction with the patient can lead to disharmony, and that can lead the patient to simply go elsewhere to seek pain medications, which will make the pain worse, which in turn leads to an escalation of narcotic drug use. This then results in more frequent visits to the emergency department, longer hospital stays, readmission for unrelenting pain and often unnecessary invasive procedures including surgery. Even in many of these scenarios, the healthcare workers may be unaware of the presence of NBS and may continue to prescribe narcotics for pain control, which leads to exacerbation of the pain.
The critical point is to establish a solid patient-doctor relationship; once trust is developed, the patient may reveal that he or she is taking opioids frequently or at high doses. In return, the healthcare worker should be non-judgemental and be empathic. One should try and address all patient concerns and expectations. These patients are often labile and because of the severe pain have unrealistic expectations; this often leads them to seek help from multiple healthcare workers and even try unproven home remedies, which in most cases results in aggravation of the syndrome. If the treatment is to succeed, then one must motivate the patient. Thoroughly listening and appreciating patient concerns are vital to reducing resistance and improving outcomes. The healthcare worker should closely watch patient cues and be honest in communications.
Withdrawal and Detoxification
There is no specific therapy for treatment of NBS; the only recommended treatment for NBS is reduction or discontinuation of the opioid. To manage the pain, one may need to prescribe antidepressants and combine it with non-pharmacological therapies. The majority of patients may benefit from psychological support while transitioning from opioid reduction to non-opioid therapies. The principle behind treating NBS rests on reduction or gradual tapering of the narcotics and detoxification. The opioid is gradually withdrawn over a few days/weeks, and at the same time, one may need to treat the withdrawal symptoms and have alternative means to manage the pain. One case report suggests that when NBS is diagnosed the patient should be started on a long-acting opioid like methadone for pain relief. Then the patient should be started on drugs to prevent withdrawal symptoms like clonidine, lorazepam and/or duloxetine. The authors claim that it is easier to taper off the long-acting opioids over several weeks compared to the short-acting drugs like morphine; in addition, the withdrawal symptoms are more manageable.
The drugs of choice to treat patients with NBS are the antidepressants. These drugs have also been used successfully to treat pain associated with irritable bowel syndrome.
The tricyclic drug should be started before the opioid is tapered or discontinued. Once the antidepressant is started, it should be continued indefinitely. The tricyclics do not work immediately but take a few weeks to reach peak therapeutic effect. The use of the antidepressants results in a positive mental effect, improved mood and general well being of the individual. More important these agents also increase the threshold for pain. The lowest dose of the tricyclic should be started and gradually titrated until a response is seen. The newer generation of serotonin reuptake inhibitors is recommended because they tend to have fewer adverse effects compared to the older tricyclic antidepressants. In some people, the adverse effects of sedation, weight gain, and worsening constipation may lead to poor compliance with the older agents. Lower doses of the tricyclic antidepressants are helpful in decreasing pain but higher doses to improve mood are often associated with many adverse effects. The newer serotonin-norepinephrine reuptake inhibitors like venlafaxine, duloxetine, desvenlafaxine, and milnacipran have all been shown to be effective in easing the pain, along with their positive effects on mood.
In several studies, both milnacipran and duloxetine have been shown to lower the need for opioids for pain control. Unfortunately, all the available antidepressants do not work consistently in all patients with NBS, and it is difficult to know who will respond to these agents. The other difficulty is that since these agents do not work right away, it may take weeks or months of therapy before one can determine if the antidepressant is working, which can lead to unnecessary expense for the patient.
Both medium and long-acting benzodiazepines like clonazepam or lorazepam can be used to manage the opioid withdrawal phase. These drugs have anti-anxiolytic properties and also have a calming effect. Prior to starting the opioid tapering, the patient should be started on an oral or intravenous benzodiazepine. Once the withdrawal is complete, the benzodiazepine should also be discontinued to prevent physical dependence. It is highly recommended that the patient is monitored while on benzodiazepines because the drugs can cause sedation and hypotension, when administered intravenously.
Clonidine is an alpha-2 adrenergic receptor agonist which has been used to manage NBS. The drug does possess anti-anxiolytic properties and helps ease the withdrawal symptoms like muscle pain, restlessness, and chills. Clonidine at doses between 0.1 to 0.4 mg per day is usually started after the opioid dose is reduced by 50% and then the dose is titrated to prevent hypotension. Studies show that clonidine can prevent the withdrawal symptoms and prevent the hyperalgesia of NBS.
For patients with NBS who fail to respond to the above drugs or continue to have pain, then one may try the off-label use of mood stabilizers (anticonvulsants) or atypical antipsychotics. Pregabalin has been used with some success in the treatment of fibromyalgia, and neuropathic pain and the agent has also been shown to lower the need for opioids in post-surgery patients. It is believed that this anticonvulsant acts by lowering glutamate levels and reducing inflammation in the nerves. Anecdotal reports suggest that gabapentin may also be useful in the treatment of NBS in a select group of patients. Until randomized clinical trials are done, the role of these agents remains experimental.
Other promising agents used to treat refractory pain in patients with NBS include the atypical antipsychotic drug quetiapine, which has been shown to ease the pain in patients with irritable bowel syndrome and fibromyalgia. The drug can also relieve anxiety and stabilize mood, but the quetiapine also has adverse effects which must be taken into account. Even after short-term use, the drug can cause significant weight gain, extrapyramidal symptoms, metabolic syndrome, and sedation. Recently anecdotal reports suggest that the N-methyl D-aspartate (NMDA) antagonist, memantine, may help relieve pain in patients being weaned off opioids.
Besides pharmacological therapy, patients with NBS must also be managed with non-pharmacological therapies. Patients with NBS have significant psychosocial issues, and behavior therapy may be beneficial. Reports indicate that a positive relationship between the healthcare provider and the patient can help prevent opioid recidivism and decrease the need for pain medications. Cognitive behavior therapy and hypnosis have been shown to lower pain in NBS, and their effects appear to be mediated by interfering with the parasympathetic nerves that play a role in the brain-gut axis. Studies show that in patients undergoing opioid detoxification, continued psychosocial intervention can improve outcomes in reducing opioid use and prevent release.
The one feature of NBS which must also be addressed is constipation. Opioids are notorious for causing constipation, which can significantly affect the quality of life. Healthcare workers who prescribe opioids must start a laxative at the same time to prevent constipation. Except for bulk-forming laxatives, all other types of laxatives can be used. In addition, the patient should be encouraged to change the lifestyle, drink ample water, exercise, and add roughage to diet.
To prevent electrolyte disturbance, one should not use osmotic laxatives for a prolonged time. If the constipation is severe, one may need to use the newer peripheral opioid antagonists like alvimopan or methylnaltrexone.
The difficulty in making the diagnosis of NBS is that it is often confused with opioid-induced constipation and several other GI disorders. The key difference that distinguishes NBS from other GI disorders is that the abdominal pain worsens with continued or increased opioid use. Some of the GI disorders that should be considered in the differential include the following:
In patients in whom NBS is suspected one should try and ascertain a history of chronic or high dose opioid use. In addition, one should ask about the intensity of pain with increasing dose of the opioid.
Acute opioid withdrawal must also be included in the differential because it can also present with hyperalgesia, rhinorrhea, yawning, restless, abdominal cramps, sweating, and diarrhea. In individuals with chronic opioid use, tolerance usually develops leading to the need for higher doses of the medication to obtain the same therapeutic effect thus making it more difficult to make a diagnosis of NBS.
NBS is underdiagnosed for several reasons. Since Opioids can affect the gastrointestinal system in many ways, the abdominal pain may be attributed to any number of causes. Plus, there is not too much literature on the topic, and hence many healthcare workers are unaware of it.
Finally, because the list of ailments that cause abdominal pain is enormous, it is a time-consuming process to determine the actual cause. Since, in most cases, the pain is not surgical, many patients are worked up as outpatients and often get lost to follow up.
While several opiate pain management strategies do exist, their application in patients with NBS has not been widely accepted. There is hope that use of the peripheral opiate receptor blockers may prove to be useful, but until clinical trials are done, this remedy remains experimental. Work is underway to develop newer anti-inflammatory agents like ketotifen, which is a mast cell stabilizer, or agents that target the astrocytes and or microglia.
There is no question that opioids are important drugs for the management of moderate to severe chronic pain, but at the same time, these drugs also have a number of adverse effects, one of which is the NBS. Because the connection between opioids and increasing abdominal pain is not always recognized, these individual are often prescribed higher doses of opioids which makes the syndrome even worse. This lack of awareness leads to a vicious cycle of pain, repeated emergency department visits and hospital admissions, use of escalating doses of opioids, increased costs, and risk of more adverse reactions. The only definite way to make the diagnosis of NBS is to make a correlation between the use of opioids and the pain intensity. The use of opiates is undergoing scrutiny in the US but in the meantime, all healthcare workers who prescribe opiates need to be aware of NBS. The pharmacist may be the first one to recognize the high doses of opiates and should educate the patient about the potential adverse effects. The nurse may also be the first one to note the presence of severe constipation and abdominal pain. Once NBS has developed, there is no good effective treatment. A pain consultant and a gastroenterologist should be consulted in the management of these patients. No matter what treatment one utilizes, it is important to enroll the patient in a long-term psychotherapy program to prevent relapse and improve the quality of life. (Level V)
Recent studies indicate that narcotic bowel syndrome appears to be more prevalent than once thought. Because of improved awareness and better recognition of the connection between opioid dose and abdominal pain, healthcare workers have now started to address the disorder. Now that there is more awareness of NBS, there is hope that more research will be conducted to determine trigger factors and the best way to manage the condition. However, there are not many long-term studies of patients managed for NBS. Whether withdrawal of opioids leads to better pain control and an improved quality of life remains debatable. There remain a significant number of patients with NBS who remain undiagnosed and are managed unnecessarily with other pharmacological therapies such as proton pump inhibitors, laxatives, and antacids. Until more comprehensive guidelines on the management of pain without opioids are developed, NBS will continue to persist. (Level V)
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