Narcotic Bowel Syndrome

Narcotic Bowel Syndrome


Douglas A. Drossman, M.D.Co-Director

UNC Center for Functional GI & Motility DisordersChapel Hill, NC, USA

Douglas A. Drossman, M.D.Co-Director

UNC Center for Functional GI & Motility DisordersChapel Hill, NC, USA

Adverse Effects of Opioids on the BowelAdverse 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

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;5:1126-1139Mehendale, Yuan. Dig Dis 2006;24:105–112Pappagallo. Am J Surg 2001;182:11S–18S Grunkenmeier et al. Clin Gastro Hep 2007;5:1126-1139Mehendale, Yuan. Dig Dis 2006;24:105–112 21242124

Narcotic Bowel SyndromeNarcotic Bowel Syndrome

A Case of Narcotic Bowel Syndrome Successfully Treated with ClonidineVoishim Wong, George Sobala, and Monty LosowskyPostgrad Med Journal 1994; 70:138

A Case of Narcotic Bowel Syndrome Successfully Treated with ClonidineVoishim Wong, George Sobala, and Monty LosowskyPostgrad Med Journal 1994; 70:138

Editorial: The Narcotic Bowel SyndromeM. Rogers and J. Cerda, J Clin Gastroenterol, 1989; 11(2):132

Editorial: The Narcotic Bowel SyndromeM. Rogers and J. Cerda, J Clin Gastroenterol, 1989; 11(2):132

Narcotic Bowel Treated with ClonidineJohn E. Sandgren, Mark S. McPhee, and Norton J. GreenbergerAnn of Int Med 1984; 101:331

Narcotic Bowel Treated with ClonidineJohn E. Sandgren, Mark S. McPhee, and Norton J. GreenbergerAnn of Int Med 1984; 101:331

19871987


Grunkemeier, DMS et al., Clin Gastroenterology and Hepatology 2007; 5:1126Grunkemeier, DMS et al., Clin Gastroenterology and Hepatology 2007; 5:1126

The Narcotic Bowel Syndrome: Clinical Features, Pathophysiology, and Management*

David M. S. Grunkemeier, Joseph E. Cassara, Christine B. Dalton, and Douglas A. Drossman

The Narcotic Bowel Syndrome: Clinical Features, Pathophysiology, and Management*

David M. S. Grunkemeier, Joseph E. Cassara, Christine B. Dalton, and Douglas A. Drossman

19881988

* “Seminal paper” for 2007 – American College of Physicians

* “Seminal paper” for 2007 – American College of Physicians

Typical Clinical Presentation for NBSTypical 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)

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; 5:1126Grunkenmeier et al. Clin Gastro Hep 2007; 5:112621252125

Case 1: NBD Developing in FBDCase 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

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; 5:1126Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007; 5:1126 21262126

Functional Pain Disorders Particularly Vulnerable to Being Treated with Narcotics

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

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;164:1773-1780Lembo A et al. CGH 2005;3:717–725Spiegel et al. Arch Intern Med 2004;164:1773-1780Lembo A et al. CGH 2005;3:717–725

Grunkemeier D.M.S. et al. CGH 2007, 5:1126Gray DW et al. Br J Surg 1987;74:239–242Grunkemeier D.M.S. et al. CGH 2007, 5:1126Gray DW et al. Br J Surg 1987;74:239–242

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Case 2: NBS with Crohn’s DiseaseCase 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

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


Case 2: NBD with Crohn’s DiseaseCase 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)

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)


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

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


Case 3: NBD Developing PostoperativelyCase 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 laterperitonitis from anastamotic perforation3rd surgery Continued in hospital for 2 months on 406080 mg/day IV

morphine sulfate for severe pain n/v with “pseudo-obstruction GI consult diagnosed NBS and patient detoxified over 6 days Patient dischargedcontinued abdominal pain, bloating for 1 yr No difficulties over subsequent 10 years

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 laterperitonitis from anastamotic perforation3rd surgery Continued in hospital for 2 months on 406080 mg/day IV

morphine sulfate for severe pain n/v with “pseudo-obstruction GI consult diagnosed NBS and patient detoxified over 6 days Patient dischargedcontinued abdominal pain, bloating for 1 yr No difficulties over subsequent 10 yearsGrunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007; 5:1126Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007; 5:1126 21312131

NBS Can Occur in Otherwise Healthy PersonsNBS 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

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


Challenges for Physicians 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

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; 5:1126Drossman DA. Am J Gastroenterol 1997; 92:1418Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007; 5:1126Drossman DA. Am J Gastroenterol 1997; 92:1418

21332133

Challenges for Physicians (cont.)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

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; 13:330Drossman DA. Gastroenterology 2004; 126:952Turk DC et al. Clin J Pain 1997; 13:330Drossman DA. Gastroenterology 2004; 126:952 21342134

PainPain



Maladaptive Therapeutic Interaction


NarcoticsNarcoticsNarcoticsNarcotics

Patient Frustration

Patient Frustration

“Negative” evaluations“Negative” evaluations

Increased Healthcare Utilization


Emergency Room VisitsEmergency Room Visits

Healthcare / Societal

Pressures


Pressures

Physician FrustrationPhysician

Frustration

“Furor Medicus”

“Furor Medicus”

Vicious Cycleof Patient - Physician

Interactions


Interactions


1888b1888b

Narcotic Prescribing in the Health Care Setting The USA (4.6% of world population) prescribes 80% of world’s opioids.

19972002: >400% increase in retail sales of oxycodone and methadone

19931999: 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

The USA (4.6% of world population) prescribes 80% of world’s opioids.

19972002: >400% increase in retail sales of oxycodone and methadone

19931999: 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


Retail Sales of Opioid Medications 1997-2002

Retail Sales of Opioid Medications 1997-2002

1997 2002 % change

Morphine 5,922,872 10,264,264 73.3

Hydrocodone 8,669,311 18,822,618 117.1

Oxycodone 4,449,562 22,376,891 402.9

Methadone 518,737 2,649,559 410.8

1997 2002 % change

Morphine 5,922,872 10,264,264 73.3

Hydrocodone 8,669,311 18,822,618 117.1

Oxycodone 4,449,562 22,376,891 402.9

Methadone 518,737 2,649,559 410.8

Trescot et al. Pain Physician 2006; 9(1):1Trescot et al. Pain Physician 2006; 9(1):121362136

Opiate Prescriptions in Ambulatory Visits NHAMCS 1994-2005

Choung et al. in preparationChoung et al. in preparation

%Ambullatory

visits

%Ambullatory

visits

11

22

77

1994 - 1995

1994 - 1995

44

66

88

55

33

00

1996 - 1997

1996 - 1997

1998 - 1999

1998 - 1999

2000 - 2001

2000 - 2001

2002 - 2003

2002 - 2003

2004 - 2005

2004 - 2005

21382138

Drug Abuse Related Emergency Department VisitsDrug Abuse Related Emergency Department Visits

US Department of Health and Human Services. April 2004Trescot et al. Pain Physician. 2006 Jan; 9(1):1-39US Department of Health and Human Services. April 2004Trescot et al. Pain Physician. 2006 Jan; 9(1):1-39

100,000100,000

1995199500

19961996 19981998 19991999 20002000 20022002

110,000110,000

80,00080,000

60,00060,000

40,00040,000

20,00020,000

19971997 20012001

Narcotic analgesicsBenzodiazepinesNarcotic analgesicsBenzodiazepines

VisitsVisits

21402140

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 usehyperalgesia 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

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 usehyperalgesia 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

Grunkemeier D.M.S. et al. CGH 2007; 5:1126Grunkemeier D.M.S. et al. CGH 2007; 5:1126Crain SM et al. Pain 2000; 84:121Crain SM et al. Brain Res 1992; 575:Crain SM et al. Pain 2000; 84:121Crain SM et al. Brain Res 1992; 575:

Potential Physiological Mechanisms for NBSPotential Physiological Mechanisms for NBS

21412141

aa

HyperalgesiaHyperalgesia

Gs

bb cc

Low-dose opioid1-10 nM

Low-dose opioid1-10 nM

High-dose opioid>1 M

High-dose opioid>1 M

Chronic opioid use

Chronic opioid use

Low-dose masks inhibitory effects

Low-dose masks inhibitory effects

High-dose masks excitatory effects

High-dose masks excitatory effects

Sensitized excitatory receptor

Sensitized excitatory receptor

Tolerance to

inhibitory receptor

Tolerance to

inhibitory receptor

AnalgesiaAnalgesia HyperalgesiaHyperalgesia

GsGo

Gi

GoGo GoGoGsGs

GiGiGiGi

InhibitoryInhibitoryExcitatoryExcitatory

InhibitoryInhibitoryExcitatoryExcitatory InhibitoryInhibitory ExcitatoryExcitatory

18901890

Potential Physiological Mechanisms for NBSPotential Physiological Mechanisms for NBS 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

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; 92:1982Grunkemeier 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

21422142

Glia of Brain and Spinal CordMicrogliaMicroglia AstrocytesAstrocytes

22842284

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;7:98Grunkemeier 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

Potential Physiological Mechanisms for NBSPotential Physiological Mechanisms for NBS 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

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

21432143

Effects of Opioids on Glia and PainEffects of Opioids on Glia and Pain

Hutchinson M et al. Scientific World J 2007; 7:98Hutchinson M et al. Scientific World J 2007; 7:98

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.





22852285

TLR4

Opioids: Neuronal Analgesia and Glial Activation

AnalgesiaAnalgesia

IL-1IL-1IL-1IL-1

IL-1IL-1

IL-1IL-1

IL-1IL-1IL-1IL-1

IL-1IL-1

IL-1IL-1

IL-1IL-1

IL-1IL-1ANALGESIAANALGESIAHutchinson M et al. Scientific World J 2007;7:98Hutchinson M et al. Scientific World J 2007;7:98 22862286





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





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

Effects of Opioids on Glia and PainEffects of Opioids on Glia and Pain

Hutchinson M et al. Scientific World J 2007; 7:98Hutchinson M et al. Scientific World J 2007; 7:98 22872287

ANALGESIAANALGESIA

Potential Benefit of Opioid Antagonists

IL-1IL-1

IL-1IL-1

IL-1

Hutchinson M et al. Scientific World J 2007;7:98Hutchinson M et al. Scientific World J 2007;7:98 22882288

IL-1

TLR4

Dorsal horn

glial cell

Dorsal horn

glial cell

Neuron-to-glia chemokineFractalkine

Neuron-to-glia chemokineFractalkine

Sensory afferent neuronATP, NO, SP, CGRP

Sensory afferent neuronATP, NO, SP, CGRP

Immune / infectious challenges

Virus, bacteria, trauma

Immune / infectious challenges

Virus, bacteria, traumaCNS signalsCNS signals

Chronic opiod usePro-inflammatory cytokine,

dynorphin release

Chronic opiod usePro-inflammatory cytokine,

dynorphin release

Other glial cells

Other glial cells

Proinflammatory cytokines, PG, NO excitatory amino acidsProinflammatory cytokines, PG, NO excitatory amino acids

Enhanced painEnhanced pain

Neuron excitability upregulates NMDA releaseNeuron excitability upregulates NMDA release

18891889

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*

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*

Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007, 5:1126Grunkemeier D.M.S. et al. Clin Gastro and Hepatology 2007, 5:1126

Chronic or frequently recurring abdominal pain treated with acute high dose or chronic narcotics and:

Diagnostic Criteria: Narcotic Bowel SyndromeDiagnostic Criteria: Narcotic Bowel Syndrome

* 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* 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

21442144

PainPain





NarcoticsNarcoticsNarcoticsNarcotics

Patient Frustration

Patient Frustration

“Negative” evaluations“Negative” evaluations



Emergency Room VisitsEmergency Room Visits


Pressures


Pressures

Physician FrustrationPhysician

Frustration

“Furor Medicus”

“Furor Medicus”

NBS treatment, Narcotics withdrawal

NBS treatment, Narcotics withdrawal


Interactions


Interactions


1888a1888a

Narcotic Withdrawal ProtocolNarcotic Withdrawal Protocol

Physician – Patient RelationshipPhysician – Patient Relationship

-3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 . . . 21-3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 . . . 21Day of taperDay of taper

18871887

Accept the pain as real (validate) and treatable

“I can see the pain has really affected your life”

“We can work together on this”

Accept the pain as real (validate) and treatable

“I can see the pain has really affected your life”

“We can work together on this”

Clinician-Patient Process and TechniquesClinician-Patient Process and Techniques

21452145

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?”

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?”


21462146

482

Clinician-Patient Process and TechniquesClinician-Patient Process and Techniques 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)”

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)” 21472147

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

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


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Clinician-Patient Process and TechniquesClinician-Patient Process and Techniques 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

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 22102210

Clinician-Patient Process and TechniquesClinician-Patient Process and Techniques 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?”

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?”

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Accept pain as real and treatable Elicit patients concerns/expectations Provide information through a dialog Present the withdrawal program Gauge the patient’s response



PEG 3350 17g PO BIDPEG 3350 17g PO BID

TCA or SNRITCA or SNRI


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Tricyclics (e.g., Desipramine, Nortriptyline, Amitriptyline)Pain benefitSide effects (sedation, constipation) reduce adherence20 amines (desipramine/nortriptyline) have fewer side effects

SNRIs (e.g., Duloxetine, Venlafaxine, Desvenlafaxine)Pain benefitNausea side effectsSpecific 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) Specific effects

Tricyclics (e.g., Desipramine, Nortriptyline, Amitriptyline)Pain benefitSide effects (sedation, constipation) reduce adherence20 amines (desipramine/nortriptyline) have fewer side effects

SNRIs (e.g., Duloxetine, Venlafaxine, Desvenlafaxine)Pain benefitNausea side effectsSpecific 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) Specific effects

Antidepressants

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Lorazepam 1mg PO q 6hrs. Lorazepam 1mg PO q 6hrs.


Morphine equiv. Dose (mg)Morphine equiv. Dose (mg) 220 200 180 160 140 120 100 80 60 40 20 0220 200 180 160 140 120 100 80 60 40 20 0

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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)

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)

Narcotic Withdrawal

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Accept pain as real and treatableElicit patients concerns/expectationsProvide information through a dialogPresent the withdrawal programGauge the patient’s response

Accept pain as real and treatableElicit patients concerns/expectationsProvide information through a dialogPresent the withdrawal programGauge the patient’s response




Lorazepam 1mg PO q 6hrs. Lorazepam 1mg PO q 6hrs.

Clonidine 0.1mg PO q 6 hrs.Clonidine 0.1mg PO q 6 hrs.


Morphine equiv. Dose (mg)Morphine equiv. Dose (mg) 220 200 180 160 140 120 100 80 60 40 20 0220 200 180 160 140 120 100 80 60 40 20 0

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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

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

Centrally Acting Augmentation

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“If I don’t think it’s going to work, will it still work?”“If I don’t think it’s going to work, will it still work?” 20212021

When Will Program Work?When Will Program Work? The patient

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

The patient 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

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Interferences With Successful OutcomeInterferences 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”)

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”)

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Seeks additional help elsewhereMay 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

Seeks additional help elsewhereMay 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

Interferences With Successful OutcomeInterferences With Successful Outcome

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Case 4: Unsuccessful TreatmentCase 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

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 21532153

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

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

Case 4: Unsuccessful Treatment, Con’t.Case 4: Unsuccessful Treatment, Con’t.

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Case 4: Unsuccessful Treatment (cont.)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

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 21612161

Summary – Narcotic Bowel SyndromeSummary – 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

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

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

Narcotic Bowel Syndrome

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