Narcotic Bowel Syndrome

Narcotic Bowel Syndrome
Douglas A. Drossman, M.D. Co-Director UNC Center for Functional GI & Motility Disorders Chapel Hill, NC, USA

Adverse Effects of Opioids on the Bowel
Opioid bowel dysfunction (OBD) Constipation, nausea, vomiting, bloating, ileus, and sometimes pain Narcotic bowel syndrome (NBS) Abdominal pain is the predominant symptom Progressive and paradoxical increase in pain despite continued or escalating dosages of narcotics prescribed to relieve the pain Underrecognized Pappagallo. Am J Surg 2001;182:11S–18S Grunkenmeier et al. Clin Gastro Hep 2007;5: Mehendale, Yuan. Dig Dis 2006;24:105–112 2124

A Case of Narcotic Bowel Syndrome Successfully Treated with Clonidine Voishim Wong, George Sobala, and Monty Losowsky Postgrad Med Journal 1994; 70:138 Editorial: The Narcotic Bowel Syndrome M. Rogers and J. Cerda, J Clin Gastroenterol, 1989; 11(2):132 Narcotic Bowel Treated with Clonidine John E. Sandgren, Mark S. McPhee, and Norton J. Greenberger Ann of Int Med 1984; 101:331 1987 3

The Narcotic Bowel Syndrome: Clinical Features, Pathophysiology, and Management* David M. S. Grunkemeier, Joseph E. Cassara, Christine B. Dalton, and Douglas A. Drossman * “Seminal paper” for 2007 – American College of Physicians Grunkemeier, DMS et al., Clin Gastroenterology and Hepatology 2007; 5:1126 1988

Typical Clinical Presentation for NBS
Patient presents with chronic or recurrent abdominal pain which is treated with narcotics Narcotics may have relieved pain initially but then tachyphylaxis occurs Pain worsens when the narcotic effect wears off Shorter pain-free periods result in increasing narcotic doses Increasing doses further alter motility and aggravate pain Can occur with in patients FGID, organic disease or otherwise health subjects (e.g., post operative) Grunkenmeier et al. Clin Gastro Hep 2007; 5:1126 2125

Case 1: NBD Developing in FBD
42 yo woman with h/o IBS for > 20yrs but worsening lower abdominal pain x 3 yrs PCP was prescribing oxycodone (10 mg tid) for pain and clonazepam and paroxetine for anxiety and depression Pain seemed different from her more typical IBS symptoms: more persistent and not relieved by defecation Pain associated with abdominal bloating, nausea, vomiting, and depressive symptoms Twice tried to stop narcotics but was unsuccessful due to increasing pain Was placed on outpatient detoxification and 1 year later she remained off narcotics with only mild IBS symptoms Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007; 5:1126 2126

Functional Pain Disorders Particularly Vulnerable to Being Treated with Narcotics
Abdominal pain is a key feature and associated with: Pain is a strong predictor of health care seeking 43% of patients admitted for abdominal pain are discharged from hospitals with no specific explanation for their pain Perception of no other treatment options Narcotics are more likely prescribed when symptoms are severe and patient demands pain relief Spiegel et al. Arch Intern Med 2004;164: Lembo A et al. CGH 2005;3:717–725 Grunkemeier D.M.S. et al. CGH 2007, 5:1126 Gray DW et al. Br J Surg 1987;74:239–242 2127

Case 2: NBS with Crohn’s Disease
20 yo woman with a 16 mo h/o narcotic use (methadone 260 mg/d) for low back pain Admitted with obstipation; methadone tapered to 230 mg/d and enemas given 3 days later, patient returned with N/V, RLQ pain Studies: CT scan: short segment of TI thickening and retained fecal material Colonoscopy: congested TI without obstruction; biopsies showed mild chronic active ileitis SBFT:20 cm of thickened, non-obstructing TI Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007; 5:1126 2128

Case 2: NBD with Crohn’s Disease
Narcotics reinstituted for pain presumed due to Crohn’s disease and pain got worse The GI service was consulted and determined that although the patient had Crohn’s disease, the pain pattern was related clinically to NBS Corticosteroids and 5-ASA were started and methadone was tapered gradually over 11 days Pain improved with withdrawal of narcotics Patient continued to use narcotics  worsening pain that improved with withdrawal of narcotics (unrelated to CD activity) Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007; 5:1126 2129

NBS Can Occur in Organic GI disorders
The pain is attributed to an underlying disease The physician feels justified to use narcotics even when disease activity is not sufficient to explain pain Assessment of disease activity relative to the patient’s pain behavior is needed Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007; 5:1126 2130

Case 3: NBD Developing Postoperatively
40 yo lawyer admitted with severe abdominal pain, n/v fever No history of previous GI symptoms Severe RLQ tenderness and leukocytosis  surgery  normal Postoperatively given 40 mg/day of IV Morphine Sulphate 2 weeks later increasing pain and obstipation; x-ray showed partial small bowel obstruction  2nd surgery 6 cm. small bowel resected due to adhesions and SBO 1 wk laterperitonitis from anastamotic perforation3rd surgery Continued in hospital for 2 months on 406080 mg/day IV morphine sulfate for severe pain n/v with “pseudo-obstruction GI consult diagnosed NBS and patient detoxified over 6 days Patient dischargedcontinued abdominal pain, bloating for 1 yr No difficulties over subsequent 10 years Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007; 5:1126 2131

NBS Can Occur in Otherwise Healthy Persons
Can occur postoperatively from high dosages of IV narcotics Narcotics are justified because the pain and N/V is attributed to surgical injury and postoperative ileus Surgery  visceral hypersensitivity  enhanced pain Increased narcotics  ileus  pseudoobstruction NBS develops Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007; 5:1126 2132

Challenges for Physicians
Physicians are ambivalent about prescribing narcotics for non-malignant chronic pain Patient’s requests for pain relief  difficult dialog about narcotic use. This can interfere with discussion of other treatment options The physician may then feel unwilling or unable to manage the clinical condition  negative interaction Patient may feel hopeless and angry at the physician when the request for narcotics is rejected Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007; 5:1126 Drossman DA. Am J Gastroenterol 1997; 92:1418 2133

Challenges for Physicians (cont.)
Nonverbal communication of pain most predictive of narcotic prescribing Time constraints for clinical visit increases diagnostic testing  reduces effective communication and information gathering improper-decision making Patients may be discharged from ER or released from clinic with narcotic Rx for pain without a diagnosis or treatment plan or follow-up PCP must deal with lack of diagnosis and pressure to prescribe narcotics Turk DC et al. Clin J Pain 1997; 13:330 Drossman DA. Gastroenterology 2004; 126:952 2134

Pain Vicious Cycle of Patient - Physician Interactions
Narcotic Bowel Syndrome Pain Narcotics Narcotics Vicious Cycle of Patient - Physician Interactions Maladaptive Therapeutic Interaction Narcotic Bowel Syndrome Physician Frustration Patient Frustration “Furor Medicus” “Negative” evaluations Healthcare / Societal Pressures Increased Healthcare Utilization Emergency Room Visits 1888b

Narcotic Prescribing in the Health Care Setting
The USA (4.6% of world population) prescribes 80% of world’s opioids. 19972002: >400% increase in retail sales of oxycodone and methadone 19931999: 100% increase in hydrocodone associated ED visits Prescribing has shifted from acute severe pain or palliative care of malignancies to prolonged use in chronic nonmalignant pain (e.g. IBD, FGIDs) Pain treatment centers shifted to narcotic treatments for non-malignant pain  emphasizes “quick fix” over multidisciplinary pain treatment There is no scientific evidence for long-term benefit of narcotics in non- malignant pain Greater sensitivity of bowel in FGIDs  more side effects from narcotics These changing practice patterns are enabled by 3rd party payers due to greater cost benefit with shorter visits and expensive delivery systems The net effect is increased annual health care expenditures Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007; 5:1126 2135

Retail Sales of Opioid Medications 1997-2002
% change Morphine 5,922,872 10,264, Hydrocodone 8,669,311 18,822, Oxycodone 4,449,562 22,376, Methadone , ,649, Trescot et al. Pain Physician 2006; 9(1):1 2136

Opiate Prescriptions in Ambulatory Visits NHAMCS 1994-2005
7 4 6 8 5 3 % Ambullatory visits Choung et al. in preparation 2138

Drug Abuse Related Emergency Department Visits
100,000 1995 1996 1998 1999 2000 2002 110,000 80,000 60,000 40,000 20,000 1997 2001 Narcotic analgesics Benzodiazepines Visits US Department of Health and Human Services. April 2004 Trescot et al. Pain Physician Jan; 9(1):1-39 2140

Potential Physiological Mechanisms for NBS
Bimodal (Excitatory/Inhibitory) Opioid Modulation in Dorsal Horn Activation of opioid receptors generally considered to inhibit afferent neurons  reduced signaling (via Gi/Go protein receptor) Newly identified Gs protein excitatory receptor  hyperalgesia Gs excitatory receptor activates with low dose opioids (1-10ηmol/L) or and acutely is inhibited with high dose opioids (>1μmol/L) Gi/Go inhibitory receptor activates with high dose opioids but is inhibited with chronic opioid use Chronic opioid usehyperalgesia due to Gi/Go inhibition and Gs activation Low dose narcotic antagonists (e.g. Suboxone–buprenorphine/naloxone)  analgesia with lower dosages by blocking Gs protein excitatory activation Crain SM et al. Pain 2000; 84:121 Crain SM et al. Brain Res 1992; 575: Grunkemeier D.M.S. et al. CGH 2007; 5:1126 2141

Hyperalgesia Analgesia Hyperalgesia
b c Low-dose opioid 1-10 nM High-dose opioid >1 mM Chronic opioid use Gi Gi Gi Go Go Go Gs Gs Gs Inhibitory Inhibitory Inhibitory Excitatory Excitatory Excitatory Low-dose masks inhibitory effects High-dose masks excitatory effects Tolerance to inhibitory receptor Sensitized excitatory receptor Hyperalgesia Analgesia Hyperalgesia 1890

Bimodal (Excitatory/Inhibitory) Opioid Modulation in Dorsal Horn Descending Pain Facilitation at RVM and via Dynorphin and CCK Activation Cingulate and prefrontal cortex and rostral ventral medulla (RVM) and PAG modulate incoming pain signals at the level of the spinal cord These areas can produce antinociception via descending inhibitory pathways RVM in particular can activate descending tracts to enhance nociception at the spinal cord Dynorphin (endogenous opioid) is found in inflammatory conditions, with nerve injury or in opiate induced pain states increases excitatory neurotransmitters from primary afferent neurons Cholecystokinin (CCK) and CCK receptors in CNS overlap with distribution of opioid peptides and can facilitate descending pain pathways Grunkemeier D.M.S. et al. CGH 2007; 5:1126 Porreca F et al. Trends Neurosci 2002; 25:319 Vanderah TW et al. J Neurosci 2000; 20:7074 Heinricher MM et al. J Neurophysiol 2004; 92:1982 2142

Glia of Brain and Spinal Cord
Microglia Astrocytes However, we are now conducting research in an time where our understanding and appreciation of glia is growing at an exponential rate. Therefore, the role of glia in opioid pharmacology is of great interest to us and I hope after today a little of our excitement for this research direction will have also rubbed off on you. 2284

Bimodal (Excitatory/Inhibitory) Opioid Modulation in Dorsal Horn Descending Pain Facilitation at RVM and via Dynorphin and CCK Activation Effects of Glial Cell Activation on Pain and Facilitation by Opioids Glial cells (astrocytes and microglia) in dorsal horn can amplify pathologic pain and produce hyperalgesia Infection/chronic inflammation activates glial cells  releases inflammatory cytokines  enhances neuronal excitability Chronic narcotics bind to glia via μ receptors  release of proinflammatory cytokines Opiates can also activate dynorphin release  glial cell activation Grunkemeier D.M.S. et al. CGH 2007, 5:1126 Watkins LR et al. Trends Neurosci 2005;28:661 Hutchinson MR et al. Sci World J 2007;7:98 2143

Effects of Opioids on Glia and Pain
Opioids acutely activate neuronal receptors  analgesia Chronic opioid use “activates” glia via toll-like receptors (TLR4, TLR2) TLR dependent glial activation produces pro-inflammatory cytokines (IL-1, IL-6, TNFα) and other inflammatory mediators Inflammatory cytokines increase neuronal excitability, produce neuropathic pain, reduce opioid analgesia and chronically, lead to opioid induced hyperalgesia. Hutchinson M et al. Scientific World J 2007; 7:98 2285 25

Opioids: Neuronal Analgesia and Glial Activation
IL-1 TLR4 IL-1 IL-1 IL-1 IL-1 IL-1 IL-1 IL-1 ANALGESIA IL-1 IL-1 Analgesia 2286 Hutchinson M et al. Scientific World J 2007;7:98 26

Effects of Opioids on Glia and Pain
Opioids acutely activate neuronal receptors  analgesia Chronic opioid use “activates” glia via toll-like receptors (TLR4, TLR2) TLR dependent glial activation produces pro-inflammatory cytokines (IL-1, IL-6, TNFα) and other inflammatory mediators Inflammatory cytokines increase neuronal excitability, produce neuropathic pain, reduce opioid analgesia and chronically, lead to opioid induced hyperalgesia. Low dose opioid antagonists (e.g., naloxone) can block TLR activation of glia and enhance opioid analgesia Future pain treatment may reduce detrimental (i.e., glial inflammatory) effects while preserving beneficial (neuronal opioid receptor analgesic) effects Hutchinson M et al. Scientific World J 2007; 7:98 2287 27

Potential Benefit of Opioid Antagonists
TLR4 IL-1 IL-1 IL-1 IL-1 IL-1 IL-1 ANALGESIA 2288 Hutchinson M et al. Scientific World J 2007;7:98 28

Enhanced pain Proinflammatory cytokines, PG, NO excitatory amino acids
Neuron-to-glia chemokine Fractalkine Sensory afferent neuron ATP, NO, SP, CGRP Immune / infectious challenges Virus, bacteria, trauma Dorsal horn glial cell CNS signals Chronic opiod use Pro-inflammatory cytokine, dynorphin release Other glial cells Proinflammatory cytokines, PG, NO excitatory amino acids Neuron excitability upregulates NMDA release Enhanced pain 1889

Diagnostic Criteria: Narcotic Bowel Syndrome
Chronic or frequently recurring abdominal pain treated with acute high dose or chronic narcotics and: The pain worsens or incompletely resolves with continued or escalating dosages of narcotics There is marked worsening of pain when the narcotic dose wanes and improvement when narcotics are reinstituted (“Soar and Crash”) There is a progression of the frequency, duration and intensity of the pain episodes The nature and intensity of the pain is not explained by a current or previous GI diagnosis* * A patient may have a structural diagnosis (e.g., IBD, chronic pancreatitis, but the character or activity of the disease process is not sufficient to explain the pain Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007, 5:1126 2144

Pain Vicious Cycle of Patient - Physician Interactions
Narcotic Bowel Syndrome Pain Narcotics Narcotics Vicious Cycle of Patient - Physician Interactions Maladaptive Therapeutic Interaction Narcotic Bowel Syndrome Physician Frustration Patient Frustration “Furor Medicus” “Negative” evaluations NBS treatment, Narcotics withdrawal Healthcare / Societal Pressures Increased Healthcare Utilization Emergency Room Visits 1888a

Narcotic Withdrawal Protocol Physician – Patient Relationship
Slide 1259 – Antidepressant Treatment: Receptor Action Sites and Dose This slide compares the TCA's and SSRI's with regard to receptor sites of action and dose ranges. Although both classes of agents report similar efficacy with regard to treatment of major depression, they differ with regard to their side effect profile and their dose ranging requirements. As shown on the top rows, the TCA's vary considerably with regard to their sites of action. The action of TCA's on several receptor sites (particularly with regard to noradrenergic sites, not shown here) may contribute to the drug's benefit as a central analgesic for visceral and somatic pain. The serotonergic action (5HT) contributes to some antidepressant and anxiolytic effect. However, the activation of anticholinergic and antihistaminic sites can lead to adverse side effects including constipation, orthostatic dizziness and sedation. In contrast, the SSRI's have a more homogeneous pattern of receptor site activation (primarily 5HT - serotonergic) and this contributes to the side effects of diarrhea, diaphoresis, sexual dysfunction and agitation. With regard to dose ranging, the SSRI's have the benefit of usually achieving benefit with one fixed dose (often one pill), while the TCA's will require dose starting at a low dose and moving up to the full dose range of about 150 mg when needed. However, many studies in IBS suggest benefit with lower dosages. Drossman DA, Camilleri M, Mayer EA, et. al. AGA Technical Review on Irritable Bowel Syndrome. Gastroenterology 2002; 123:2108 Drossman DA, Creed FH, Olden KW, et. al. Psychosocial aspects of the functional gastrointestinal disorders. In: Drossman, D. A., Corazziari, E., Talley, N. J., Thompson, W. G., and Whitehead, W. E. Rome II. The functional gastrointestinal disorders: Diagnosis, pathophysiology and treatment; A multinational consensus,2 ed. Degnon and Associates, 2000: Physician – Patient Relationship Day of taper 1887 32

Clinician-Patient Process and Techniques
Accept the pain as real (validate) and treatable “I can see the pain has really affected your life” “We can work together on this” 2145

Accept the pain as real and treatable Elicit the patient’s concerns and expectations “What are your biggest worries or concerns about being on narcotics (and going off narcotics)?” “What do you expect will happen when you stop narcotics?” 2146

Accept the pain as real and treatable Elicit the patient’s concerns and expectations Provide information through a dialog: Address the patient’s stated concerns and expectations Provide a physiologic basis for the pain “Pain in the body is experienced in the brain where it can turn ‘pain volume’ up or down depending on the circumstances (give examples)” Discuss the effects of narcotics on pain and GI function “Narcotics slow the bowels producing the constipation, bloating and vomiting you are having; they also sensitize the nerves to turn up the ‘pain volume’ thus making the pain worse” Explain the rationale for and process of withdrawal “It is likely you will be better and certainly no worse when you are off the narcotics. We will be substituting other pain control methods while we gradually taper the narcotics (so you won’t be abandoned in pain)” 2147

Accept the pain as real and treatable Elicit the patient’s concerns and expectations Provide information through a dialog Present the withdrawal program Use illustrations or graphics Involve a responsible family member Indicate that someone will be available to address possible side effects or flare-ups 2148

Accept the pain as real and treatable Elicit the patient’s concerns and expectations Provide information through a dialog Present the withdrawal program Clinical setting Outpatient Patient must be highly motivated Withdrawal can take days to weeks Inpatient If complicated by nausea, vomiting, ileus or pseudo-obstruction Limited motivation or social support Requires monitoring Withdrawal can occur over several days 2210

Accept the pain as real and treatable Elicit the patient’s concerns and expectations Provide information through a dialog Present the withdrawal program Clinical setting Gauge the patient’s response Willingness to go through the program Degree of participation Keep a log? Be aware of: “Whatever you say doc” Assess Non-verbal behaviors and “meta-language” Address challenging questions “How do you know you’re still not missing something?” “What if I get a bad attack?” “What if these other medicines make me sick?” 2149

Accept pain as real and treatable Elicit patients concerns/expectations Provide information through a dialog Present the withdrawal program Gauge the patient’s response Slide 1259 – Antidepressant Treatment: Receptor Action Sites and Dose This slide compares the TCA's and SSRI's with regard to receptor sites of action and dose ranges. Although both classes of agents report similar efficacy with regard to treatment of major depression, they differ with regard to their side effect profile and their dose ranging requirements. As shown on the top rows, the TCA's vary considerably with regard to their sites of action. The action of TCA's on several receptor sites (particularly with regard to noradrenergic sites, not shown here) may contribute to the drug's benefit as a central analgesic for visceral and somatic pain. The serotonergic action (5HT) contributes to some antidepressant and anxiolytic effect. However, the activation of anticholinergic and antihistaminic sites can lead to adverse side effects including constipation, orthostatic dizziness and sedation. In contrast, the SSRI's have a more homogeneous pattern of receptor site activation (primarily 5HT - serotonergic) and this contributes to the side effects of diarrhea, diaphoresis, sexual dysfunction and agitation. With regard to dose ranging, the SSRI's have the benefit of usually achieving benefit with one fixed dose (often one pill), while the TCA's will require dose starting at a low dose and moving up to the full dose range of about 150 mg when needed. However, many studies in IBS suggest benefit with lower dosages. Drossman DA, Camilleri M, Mayer EA, et. al. AGA Technical Review on Irritable Bowel Syndrome. Gastroenterology 2002; 123:2108 Drossman DA, Creed FH, Olden KW, et. al. Psychosocial aspects of the functional gastrointestinal disorders. In: Drossman, D. A., Corazziari, E., Talley, N. J., Thompson, W. G., and Whitehead, W. E. Rome II. The functional gastrointestinal disorders: Diagnosis, pathophysiology and treatment; A multinational consensus,2 ed. Degnon and Associates, 2000: TCA or SNRI PEG g PO BID Physician – Patient Relationship Day of taper 1887 40

Antidepressants Tricyclics (e.g., Desipramine, Nortriptyline, Amitriptyline) Pain benefit Side effects (sedation, constipation) reduce adherence 20 amines (desipramine/nortriptyline) have fewer side effects SNRIs (e.g., Duloxetine, Venlafaxine, Desvenlafaxine) Nausea side effects Specific effects Duloxetine first to be marketed for “pain with depression” Venlafaxine requires higher dosage (e.g., 225 mg.) for pain benefit SSRIs (e.g., Paroxetine, Citalopram, Escitalopram) Anxiolysis (social phobia, agoraphobia, OCD) +/- pain benefit (but augments TCA effect via anxiolysis) Side effects (anxiety, diarrhea) 2060

Accept pain as real and treatable Elicit patients concerns/expectations Provide information through a dialog Present the withdrawal program Gauge the patient’s response Lorazepam 1mg PO q 6hrs. Slide 1259 – Antidepressant Treatment: Receptor Action Sites and Dose This slide compares the TCA's and SSRI's with regard to receptor sites of action and dose ranges. Although both classes of agents report similar efficacy with regard to treatment of major depression, they differ with regard to their side effect profile and their dose ranging requirements. As shown on the top rows, the TCA's vary considerably with regard to their sites of action. The action of TCA's on several receptor sites (particularly with regard to noradrenergic sites, not shown here) may contribute to the drug's benefit as a central analgesic for visceral and somatic pain. The serotonergic action (5HT) contributes to some antidepressant and anxiolytic effect. However, the activation of anticholinergic and antihistaminic sites can lead to adverse side effects including constipation, orthostatic dizziness and sedation. In contrast, the SSRI's have a more homogeneous pattern of receptor site activation (primarily 5HT - serotonergic) and this contributes to the side effects of diarrhea, diaphoresis, sexual dysfunction and agitation. With regard to dose ranging, the SSRI's have the benefit of usually achieving benefit with one fixed dose (often one pill), while the TCA's will require dose starting at a low dose and moving up to the full dose range of about 150 mg when needed. However, many studies in IBS suggest benefit with lower dosages. Drossman DA, Camilleri M, Mayer EA, et. al. AGA Technical Review on Irritable Bowel Syndrome. Gastroenterology 2002; 123:2108 Drossman DA, Creed FH, Olden KW, et. al. Psychosocial aspects of the functional gastrointestinal disorders. In: Drossman, D. A., Corazziari, E., Talley, N. J., Thompson, W. G., and Whitehead, W. E. Rome II. The functional gastrointestinal disorders: Diagnosis, pathophysiology and treatment; A multinational consensus,2 ed. Degnon and Associates, 2000: TCA or SNRI Morphine equiv. Dose (mg) PEG g PO BID Physician – Patient Relationship Day of taper 1887 42

Narcotic Withdrawal Start medium acting benzodiazepine (e.g., lorazepam) Involve psychologist to help with withdrawal program Narcotic tapering Start with maximal daily dose of medium to long acting narcotic (more frequent dosing needed for short acting opiates) Standardize all narcotics to one dose (morphine equivalents) Non-contingently reduce 10-33% each day (e.g., off on 4th day with 33% reduction qd) No prn or breakthrough dosing) 2151

Accept pain as real and treatable Elicit patients concerns/expectations Provide information through a dialog Present the withdrawal program Gauge the patient’s response Clonidine 0.1mg PO q 6 hrs. Lorazepam 1mg PO q 6hrs. Slide 1259 – Antidepressant Treatment: Receptor Action Sites and Dose This slide compares the TCA's and SSRI's with regard to receptor sites of action and dose ranges. Although both classes of agents report similar efficacy with regard to treatment of major depression, they differ with regard to their side effect profile and their dose ranging requirements. As shown on the top rows, the TCA's vary considerably with regard to their sites of action. The action of TCA's on several receptor sites (particularly with regard to noradrenergic sites, not shown here) may contribute to the drug's benefit as a central analgesic for visceral and somatic pain. The serotonergic action (5HT) contributes to some antidepressant and anxiolytic effect. However, the activation of anticholinergic and antihistaminic sites can lead to adverse side effects including constipation, orthostatic dizziness and sedation. In contrast, the SSRI's have a more homogeneous pattern of receptor site activation (primarily 5HT - serotonergic) and this contributes to the side effects of diarrhea, diaphoresis, sexual dysfunction and agitation. With regard to dose ranging, the SSRI's have the benefit of usually achieving benefit with one fixed dose (often one pill), while the TCA's will require dose starting at a low dose and moving up to the full dose range of about 150 mg when needed. However, many studies in IBS suggest benefit with lower dosages. Drossman DA, Camilleri M, Mayer EA, et. al. AGA Technical Review on Irritable Bowel Syndrome. Gastroenterology 2002; 123:2108 Drossman DA, Creed FH, Olden KW, et. al. Psychosocial aspects of the functional gastrointestinal disorders. In: Drossman, D. A., Corazziari, E., Talley, N. J., Thompson, W. G., and Whitehead, W. E. Rome II. The functional gastrointestinal disorders: Diagnosis, pathophysiology and treatment; A multinational consensus,2 ed. Degnon and Associates, 2000: TCA or SNRI Morphine equiv. Dose (mg) PEG g PO BID Physician – Patient Relationship Day of taper 1887 44

Centrally Acting Augmentation
Clonidine α2-adrenergic against with central (anxiety reduction) and peripheral (pain reduction via bowel compliance) effects Helps reduce diarrhea Prevents adrenergic effects of narcotic withdrawal Mirtazepine Serotonergic and noradrenergic drug with 5HT2 and 5HT3 effects – can have pain benefit Use with nausea, anorexia, weight loss, diarrhea Some sedation Buspirone Azaprione with anti-anxiety effects acting on non BZD GABA receptors Has 5HT1 and 5HT2 effects May augment the effect of the antidepressant Quetiapine Atypical antipsychotic in high doses with complex effects Dopamine (D1, D2) and Serotonin (5HT1a, 5HT2) antagonism and some α2-adrenergic effect Benefits include – sleep, anti-anxiety, analgesia augmentation 2152

“If I don’t think it’s going to work, will it still work?”
2021

When Will Program Work? The patient The physician
Has no history of drug seeking behavior or other substance use Recognizes the adverse effects of the narcotics Understands there are other treatment options for pain relief Is motivated at start and throughout treatment (no “bargaining”) The physician Believes in and communicates commitment to the patient and the treatment plan Is comfortable in coordinating the treatment (medications, availability) Will personally follow up or set up resources (psychologist, primary care doc, PA or FNP) to do so The treatment interaction is collaborative Health care resources are available Psychologist Primary care clinician 2155

Interferences With Successful Outcome
Negotiation (“Just one more day”) Determine if it relates to anxiety about treatment failure, ambivalence, lack of desire to continue or malingering Explore and discuss patient concerns May not have been previously addressed May fear being abandoned in the care Provide solutions Continue discussions Reduce time between dosing maintaining daily dosage Adjust or add other medications (.e.g. Ketorolac) Rapidly tapers or abruptly withdraws narcotics Patient may not have understood protocol Trying to prove he/she can do it or to “get it over with” Sabotage (“See it does not work”) 2156

Interferences With Successful Outcome
Seeks additional help elsewhere May be due to lack of trust with diagnosis Risk of seeing physicians who again prescribe narcotics Provide solutions Encourage patient to work with one treating physician Identify and communicate with other physicians involved Copy records to other physicians Be vigilant to drug seeking behaviors 2157

Case 4: Unsuccessful Treatment
26 yo medical student sent by father (prominent academic physician) for detoxification 2 year history of pain beginning acutely as sharp and severe in RLQ followed by N/V which has progressed in frequency and severity Extensive evaluation with HIDA, MRI/MRCP, ERCP, CT, Liver bx all normal Diagnosed with cyclic vomiting syndrome and Rx with amitriptyline with 8 mo relief Pain recurred while on taking night call  began taking fentanyl patch  improvement  gradual increase in dosing for relief  now self medicates 2 mg. dilaudid SQ q4 hrs. Currently with severe constipation (BM q2-3 wks), pain relieved only 1-2 hrs on narcotic, n/v Psychologist consulted to help with detoxification program Psychosocial Lost control of life because of frequent hospitalizations Engaged for 2 yrs and fiance lives out of state Current problem has delayed wedding and he has contemplated dropping out of school Brother developed appendicitis and quit medicine soon after graduation – “Best choice he ever made”; Father upset Denies stress related to symptoms or in his life; illness is “positive” – brings him closer to mother and fiance 2153

Case 4: Unsuccessful Treatment, Con’t.
Admitted for detoxification program with taper to occur by 25% daily While patient acknowledged desire to go off narcotics, he repeatedly asked what he will get if pain recurs. On 1st day before when getting full narcotic dosing he asked for delay in taper because he ate fried chicken the night before During taper he requested to leave hospital to go to his hotel room Later mother noted narcotics stashed in his room Patient’s mother reported that he told her he would go back on narcotics at home if he has pain One night before completion of taper patient reported increased pain and demanded to go back on narcotics and to slow down taper This was refused and narcotics completely tapered off That night prior to discharge the patient signed out against medical advice A follow up appointment was given in 6 weeks but patient did not return 6 months later the patient contacted Dr. Drossman stating he now felt he was ready to come off narcotics. Inpatient detoxification rescheduled 2154

Case 4: Unsuccessful Treatment (cont.)
Rehospitalized for detoxification 10/08 Psychosocial / Clinical data Claimed that had bowel obstructions from adhesions after leaving UNC – records obtained and not documented – laparoscopy showed some adhesions but no obstruction Patient said engagement was off, mother said he is still seeing her Mother closely involved in care Psychologist saw patient and saw little motivation for detox – refused several visits Protocol instituted with more delayed detox program – 15% reduction daily On 2nd day patient stated it was too fast and asked for 10% reduction – refused By 4th day patient said he was having pain and asked for “just one shot” Patient noted to house staff that after discharge he would go to ER to get pain shot if he had pain Narcotics tapered off by 6th day That evening he went down to basement of hospital to find the ER to get a pain shot. was escorted back but that evening and later found to be very sedated Patient discharged the next morning 2161

Summary – Narcotic Bowel Syndrome
NBS is a subset of opioid bowel dysfunction Chronic or recurrent abdominal pain which worsens or incompletely resolves with continued or escalating dosages of narcotics Can occur in patients with FGID or organic diseases Limitations in health care: use of narcotics for non-malignant pain, poor communication, improper decision-making and lack of recognition of NBS, contribute to escalating narcotic use Treatment involves a protocol driven detoxification that requires a motivated patient and clinical team 2158

“It sort of makes you stop and think, doesn’t it?”
1829

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