Karen H. Seal, MD, MPH

San Francisco VA Medical Center and University of California, San Francisco
 Pain/PTSD connection

 PTSD and prescription opioid risk 

 Novel therapies for patients with pain & PTSD

 Why opioids may prevent/ameliorate PTSD

 Buprenorphine for pain, PTSD, opioid use disorder

Iraq/Afghanistan 

Veterans – carry heavy combat 

equipment/body armor and 

weaponry > 100 lbs

 Chronic pain more prevalent in 

female vets3,4

 >50% with PTSD have received 

chronic pain diagnoses5

Most prevalent problem among US Veterans

1. Beckham, 1997

2. Shipherd, 2007

3. Frayne, 2011

4. Haskell, 2010 

5. Seal, 2013

50%

Female 75%

Male 

Vietnam 

66%- 80% of veterans 

with PTSD reported 

chronic pain1,2
3.6

12.9

2.5

20.1

8.6

20.8

4.5

28.4

15.8

29.3

6.5

36.1

0

5

10

15

20

25

30

35

40

Headaches/Migraine Back Pain Neck Pain Arthritis/Joint Pain

Percent of Veterans 

No MH Dx

MH Dx excluding PTSD

PTSD

% 

Seal, 2013
PTSD Diagnostic Criteria (DSM-V) 

Criteria A: Traumatic Event (> 30 days ago)

Criteria B : Re-experiencing (intrusive traumatic memories)

Criteria C : Avoidance

Criteria D : Negative alterations in cognitions and mood- persistent negative emotional state

Criteria E : Alterations in arousal and reactivity-reckless or 

destructive behavior

Criteria F: Negative impact on functioning
 Shared Vulnerability- Anxiety sensitivity/Distress intolerance

 PTSD alters HPA axis- increased inflammatory conditions

 PTSD can cause dysregulation of the autonomic nervous system, 

endogenous opioid and serotonergic systems

 Neuropeptide Y and neuroactive hormones (allopregnanolone and 

pregnanolone) help with pain control; low in individuals with pain 

and PTSD.

 PTSD decreases frontal lobe inhibition of exaggerated responses 

to pain and fear triggers.

 Mutual Maintenance- pain & anxiety maintain each other.
1. Anxiety/hyperarousal- pain perception

2. PTSD re-experiencing evokes pain

3. Avoidance/Reduced activity

disability

Disability 

PTSD

Anxiety

Pain

Adapted from Sharp and Harvey, 2001 
In patients with PTSD, 

poor pre-frontal cortical 

inhibition leads to 

dysregulated amygdala 

and limbic systems, 

which can lead to 

exaggerated responses 

to both fear and pain

stimuli. 

 Patients with pain and PTSD were 

significantly more likely to have been 

prescribed opioids for pain control than 

patients without PTSD (Phifer et al., 2011) 

 Opioids were most likely to be prescribed in 

those with the highest PTSD symptom 

severity scores. 

 (Schwartz et al., 2006) 
Mental Health Diagnostic 

Category

Opioid Prescription

n (%)

Relative Risk 

(95% CI)

No MH Diagnosis (Ref) 4488 (6.5) 1.00

MH Diagnosis (No PTSD) 3205 (11.7) 1.74 (1.67, 1.82)

PTSD 7983 (17.8) 2.58 (2.49, 2.67)

All p-values < 0.001; Relative risk adjusted for sociodemographic and 

military service characteristics

Seal et al., JAMA,2012
0

10

20

30

40

50

60

70

Opioid

prescription

Highest

quintile of

avg daily

opioid use

Duration of

opioid use >2

months

Concurrent

opioids

Concurrent

sedative

hypnotics

Early opioid

refills

Percent (%)

 No MH diagnosis MH diagnosis w/o PTSD PTSD

Seal et al., JAMA, 2012
 High rates of PTSD-SUD comorbidity. (Morasco et al., 

2010; Seal et al. 2010 )

 PTSD patients exhibit high distress about pain; PCPs 

with little training in managing PTSD prescribe 

opioids to mitigate distress. 

 Self-medication hypothesis (Bremner et al., 1996; Jakupcak 

et al., 2010) 

 Opioids blunt trauma-related negative cognitions

 Opioids inhibit ACTH and glucocorticoid release; decrease 

“stress” response

 Opioids decrease NE release from locus coeruleus (LC); 

reduce exaggerated fear response 
POMC

ACTH=

= 

Endogenous

Opioids

Glucocorticoids 

== --------------------------------------------------------------------------------------------------------

Endogenous

Opioids

- 

- NE LC= NE + CRF

Stress

- 
Overuse of 

opioids for 

chronic pain

Downregulation of 

opioid

receptors; 

opioids no 

longer inhibiting 

NE release by LC 

LC== NE + CRF

Exogenous opioids may drive “Feed-Forward” 

stress enhancing circuit in PTSD

Stress

Unopposed NE Exaggerated fear 

memory or exacerbation of PTSD 

NE

 Mostly surveys and uncontrolled case series

 RCTs of short duration with small sample sizes

 Most studies are pharma sponsored

Outcomes: 

 Better analgesia with opioids vs. placebo

 No difference with opioids vs. non-opioid

 Mixed reports on function

 Addiction not assessed

Ballantyne JC, Mao J. N Engl J Med. 2003 Nov 13;349(20):1943-53.

Kelso E, et al. Pain. 2004 Dec;112(3):372-80.

Eisenberg E, McNicol ED, Carr DB. JAMA. 2005 Jun 22;293(24):3043-52.

Furlan AD, et al. CMAJ. 2006 May 23;174(11):1589-94.

Noble M, et al. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD006605. 

Martel B, et al. Ann Intern Med. 2007 Jan 16;146(2):116-27.
 Among patients with chronic pain...

 Those who received opioids had lower 

quality of life at follow-up

 Those who received opioids were 4 times 

less likely to recover from chronic pain..

Erickson, Pain 2006; Dillie , J Am Board Fam Med 2008
 Uncertain Benefits:

 ? Pain relief

 ? Improved physical functioning, QOL

 Potential known harms:

 Tolerance/physical dependence

 Addiction/abuse/diversion

 Respiratory depression, OD

 Cognitive impairment/ somnolence

 Hypogonadism- ED, fatigue, OP, muscle wasting

 Sleep disturbances; worsening of sleep apnea

 Increased pain from withdrawal and hyperalgesia
VA patients

(fatal overdose) 

HMO patients 

(any overdose)

Dose (mg/day) Hazard Ratio (95% CI)

<20 1.0 1.0

20-49 1.9 (1.3, 2.7) 1.4 (0.6, 3.6)

50-99 4.6 (3.2, 6.7) 3.7 (1.5, 9.5)

≥ 100 7.2 (4.9, 10.7) 8.9 (4.0, 19.7)

Dunn, Annals Intern Med, 2010; Bohnert, JAMA, 2011
 Receiving prescription opioids (vs. not) was associated 

with increased risk of adverse clinical outcomes; 

particularly elevated in veterans with PTSD. 

 

 Wounds or injuries

 Opioid-related accidents 

and overdoses

 Other accidents and 

overdoses

 Self-inflicted injuries

 Violence-related injuries

Seal et al., JAMA,2012
 Drinking about 12 beers a night to “relieve pain”; 

receiving benzodiazepines for “anxiety” from outside 

doc; not receiving evidence-based PTSD treatment.

 Nightmares of combat nearly every night, poor sleep 

quality-checking doors and windows; avoids leaving 

house; no longer goes out to gym to exercise 

 LBP started in Iraq from injury. Has been on opioids in 

past for back pain. Requests MS Contin and 

oxycodone.

 This is a new patient. What do you do?
 On the one hand, desire to establish 

therapeutic alliance, relieve pain and distress 

 On the other hand, desire to do no harm
Patient-Centered Education/Universal Precautions

 Non-confrontational style; contextualize

 Assess patient’s prior experience with opioids

 Educate about risks/ questionable benefits of opioids

 Educate re: non-opioid/non-pharm alternatives/adjuncts

 If opioids used, frame as a trial with clear functional goals; 

use shared decision-making to form multi-modal “Pain 

Care Plan”

 Monitor and re-assess risk/benefit ratio (UDS, PEG, 

COMM)

 Have clear functional benchmarks; up-front agreements if 

goals not met or evidence of aberrant opioid behavior.
1. Validate

• “Real” pain

• Patient’s experience and 

efforts

3. Motivate

• Assist patient toward 

readiness for change

2. Educate

• Realistic expectations

• From “I will fix it” to “I will 

assist you in improving your 

functioning & QOL”

4. Activate

• Collaborative goal-setting
Non-opioid, non-pharmacological interventions 

should be first-line:

 Non-opioid pain medications/

procedures 

 Target sleep 

Treat PTSD comorbidities (e.g., dep, AUD) 

 PT and gentle exercise

 CAM for pain & PTSD

 CBT for pain & PTSD 
Scientific evidence on CAM 

for low back pain

Promising

evidence of 

potential benefit

Limited, mixed, or 

no evidence to 

support use

Acupuncture √

Massage √

Spinal Manipulation √

Progressive Relaxation √

Yoga √

Herbal Remedies √

From National Center for Complimentary and Alternative Medicine-NCCAM
From VA/DoD Clinical Practice Guideline for Management of 

Post-Traumatic Stress: 

• There is insufficient evidence to recommend CAM 

approaches as first line treatments for PTSD. [I]

• CAM approaches (e.g. mindfulness, yoga, acupuncture, 

massage, and others) may be considered for adjunctive 

treatment of hyperarousal symptoms

• CAM approaches may be considered as adjunctive 

approaches to address some co-morbid conditions (e.g. 

acupuncture for pain). [C]
 Strong evidence for collaborative care models that use a Care 

Manger and combine pain and mental health treatment (Dobscha et 

al.,2009; Kronke et al., 2010)

 Interdisciplinary approach used in VA PACT

 Combined CBT for pain and PTSD- promising preliminary results in 

a limited number of subjects; second study ongoing (Otis, 2009)

 Ongoing exercise trial examining changes in pain and PTSD 

symptoms and stress hormone levels (allopregnanalone and 

pregnanalone and NPY) (Scioli) 

 Shared decision-making and Care Manager telephone motivational 

coaching to promote non-opioid pain management strategies and 

decrease high-risk opioid use in complex chronic pain patients (Seal, 

NCCAM)

After trauma, patients (pediatric burn victims, adult 

trauma victims, Iraq soldiers) administered morphine 

within 48 hours were significantly less likely to develop 

PTSD and/or had less severe PTSD symptoms. 

 

 

 (Holbrook et al., 2010; Saxe, 2001; Bryant, 2009)
 After acute (mouse) trauma, infusion of a 

selective (NOP) agonist blocked fear memory 

consolidation in the amygdala. 

 Mice given NOP agonist displayed no or fewer sx 

of PTSD after trauma. 

 Selective NOP agonist spared μ opioid receptor; 

did not produce undesirable reward effects of 

opioids leading to addiction and dependence.

 Clinical implications; PEP for first responders?

 

 Andero, Ressler et al., SciTrans Med, 2013
Seal and Stein, SciTrans Med, 2013

 Buprenorphine is a partial NOP receptor agonist

 FDA-approved for opioid use disorder (SL) and 

chronic pain (transdermal patch)

 Partial μ opioid receptor agonist, high affinity, and 

long half-life produce analgesic effect and ability to 

block opioid craving 

 Less stimulation of reward pathways; lower risk for 

abuse/addiction 

 Kappa opioid receptor antagonist-explains observed 

anti-depressant/anxiolytic effects; benefits in PTSD?
Other Opioids Buprenorphine

Pain control Moderate to severe Mod to severe; 

neuropathic pain

Tolerance, physical 

dependence, withdrawal

Yes Less

Respiratory depression/OD Yes Rare

Cognitive impairment Yes Less

HPA axis dysregulation Yes No

Immunosuppression Yes No

QTc prolongation/sudden

cardiac death

Yes No

Safe in renal failure, elderly, 

hepatic dysfunction

No Yes

Drug-drug interactions Yes Few
 Published case report of incidental improvement in PTSD 

symptoms when buprenorphine was used for ORT

 Danovitch, 2009

 In a retrospective cohort of 717 Iraq and Afghanistan veterans 

with PTSD, chronic pain and SUD, those who switched from 

opioid to buprenorphine therapy (N=257) had significantly 

improved PTSD and pain symptom severity scores compared 

to controls who remained on moderately high-dose opioid 

therapy (N=460) (p-values for PTSD and pain < 0.01) 

 Seal et al., prelim data
 High pain-PTSD comorbidity observed in veterans and other 

populations.

 Those with pain and PTSD more likely to be prescribed 

opioids, have higher-risk opioid behavior & adverse outcomes.

 Evidence is accumulating for collaborative care and combined 

PTSD and chronic pain therapies (including CAM) as effective 

non-opioid pain management strategies.

 Buprenorphine (as an NOP-R agonist) may have efficacy (and 

greater safety) for refractory opioid use disorder, chronic pain 

and PTSD; more research is needed.
QUESTIONS ?

karen.seal@va.gov

karen.seal@ucsf.edu