The narcotic bowel syndrome: clinical features, pathophysiology, and management

Abstract

Narcotic bowel syndrome (NBS) is a subset of opioid bowel dysfunction that is characterized by chronic or frequently recurring abdominal pain that worsens with continued or escalating dosages of narcotics. This syndrome is underrecognized and may be becoming more prevalent. In the United States this may be the result of increases in using narcotics for chronic nonmalignant painful disorders, and the development of maladaptive therapeutic interactions around its use. NBS can occur in patients with no prior gastrointestinal disorder who receive high dosages of narcotics after surgery or acute painful problems, and among patients with functional gastrointestinal disorders or other chronic gastrointestinal diseases who are managed by physicians who are unaware of the hyperalgesic effects of chronic opioids. The evidence for the enhanced pain perception is based on the following: (1) activation of excitatory antianalgesic pathways within a bimodal opioid regulation system, (2) descending facilitation of pain at the rostral ventral medulla and pain facilitation via dynorphin and cholecystokinin activation, and (3) glial cell activation that produces morphine tolerance and enhances opioid-induced pain. Treatment involves early recognition of the syndrome, an effective physician-patient relationship, graded withdrawal of the narcotic according to a specified withdrawal program, and the institution of medications to reduce withdrawal effects.

Figure 1

Vicious cycle of patient-physician interaction in narcotic bowel syndrome. Patient presents with a pain, either due to a structural condition (e.g., IBD), post-surgery or functional GI disorder and narcotics are started. Patient develops symptom of Narcotic Bowel Syndrome. Subsequent evaluation is unrevealing and the narcotics are escalated to treat the abdominal pain with worsening of NBS. This prompts the patient to increase health care utilization or make emergency room visits, which leads to physician frustration and “furor medicusw” leading to a maladaptive therapeutic interaction with additional use of narcotics. The cycle continues until the syndrome is recognized and treatment initiated.

Figure 2

Bimodal (Excitatory and Inhibitory) Opioid Modulation System in the Dorsal Horn. Opioids appear to have differential effects on the opioid receptor in the dorsal root ganglion based on whether it activates the traditional G_I/G_O protein inhibitory mode leading to analgesia or a newly identified Gs protein excitatory receptor that can produce hyperalgesia. Figure 2a shows the effect of low dose opioids (1–10 nM), which preferentially activates the excitatory (Gs coupled) mode and masks the inhibitory (Gi/Go) mode leading to hyperalgesia. More typically high dose opioids are used (figure 2b) where there is preferential activation of the inhibitory mode and masking of the excitatory mode. With the chronic use of opioids there is again sensitization and unmasking of the excitatory mode and tolerance of the inhibitory mode leading to hyperalgesia. Low doses of opioid antagonists like naltrexone, naloxone or buprenorphone have selective inhibitory effects on the excitatory pathways which enhances morphine activity.

Figure 3

Activation of Dorsal Horn Glial Cells. The activation of spinal cord glial cells leads to hyperalgesia. This process is enabled via stimulation of glial cells to produce proinflammatory cytokines, prostaglandin, nitric oxide and excitatory amino acids, which increase neuron excitability and upregulate NMDA receptors leading to enhanced pain. Factors that activate this mechanism include. : a) release of Adenosin triphosphate (ATP), nitric oxide (NO), prostaglandins, substance P and calcitonin g-related polypeptide (CGRP) from sensory afferent neurons, b) descending signals from the CNS, c) a vicious cycle with activation from other activated glial cells, d) immune challenges or infections, and e) release of a neuron to glia chemokine, fractalkine. Importantly chronic opioid use also activates this system via release of pro-inflammatory cytokines and endogenous dynorphin release. Thus chronic opioid use in addition to these other factors can lead to hyperalgesia via this mechanism.

Figure 4

Narcotic Withdrawal Protocol for NBS. After identification of NBS and discussion with the patient (validating pain, discussion of pathophysiology and willingness to start therapy) the taper starts with a hypothetical dosage of 250 mg/day and then weaned at a 10–33% reduction rate per day. Polyethylene glycol (PEG) is used to treat constipation as needed. A tricyclic or serotonin-norepinephrine (SNRI) antidepressant is started before detoxification and continues indefinitely for pain control. Lorazepam added at the outset of therapy for withdrawal anxiety and is discontinued at the end of the narcotic taper. Clonidine is typically added after day 2 or 3 and is continued until withdrawal is completed or for several weeks later. Of paramount importance is an ongoing physician-patient relationship.