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Pain Management

Chapter 21

pain management

FREDERICK J. STODDARD, Jr, MD*; ROBERT L. SHERIDAN, MD†; JEEVENDRA MARTYN, MD‡; JAMES E. 

CZARNIK, MD§; and VIRGIL T. DEAL, MD¥

INTRODUCTION

ANATOMY OF INJURY-RELATED PAIN

BIOLOGY OF PAIN

PRINCIPLES OF PAIN THERAPY

ADVERSE EFFECTS OF PAIN

GENETICS

METHODS OF PAIN ASSESSMENT

METHODS OF PAIN MANAGEMENT: OVERVIEW

PHARMACOLOGICAL MANAGEMENT OF ACUTE PAIN

PSYCHOLOGICAL management of pain and grief

SPECIAL PROBLEMS

Ventilated Patient

Burns and Multiple Traumas

Amputation Pain

Weaning

Pediatric Pain

Psychiatric Risk Factors

Pain Management and the Issue of Addiction

THE ETHICS OF PAIN CONTROL

SUMMARY

*Associate Clinical Professor, Department of Psychiatry, Harvard Medical School at the Massachusetts General Hospital; and Chief of Psychiatry, Shriners 

Burn Hospital, 51 Blossom Street, Boston, Massachusetts 02114; Formerly, Senior Surgeon, US Public Health Service

†

Associate Professor, Department of Surgery, Harvard Medical School at the Massachusetts General Hospital; and Assistant Chief of Staff, Shriners Burn 

Hospital, 51 Blossom Street, Boston, Massachusetts 02114; formerly, Lieutenant Colonel, Medical Corps, US Army; US Army Institute of Surgical 

Research, Brooke Army Medical Center, San Antonio, Texas

‡

Professor/Chief, Department of Anesthesiology and Critical Care, Harvard Medical School/Shriners Hospital for Children, 51 Blossom Street, Room 

206, Boston, Massachusetts 02114

§

Colonel, Medical Corps, US Army; Command Surgeon, Joint Special Operations Command, PO Box 70239, Fort Bragg, North Carolina 28307-5000; 

formerly, Deputy Command Surgeon, US Army Special Operations Command, Fort Bragg, North Carolina

¥

Colonel, Medical Corps, US Army; United States Special Operations Command, 7701 Tampa Point Boulevard, MacDill Air Force Base, Florida 33621-

5323; formerly, Commander, Walter Reed Health Care System, Washington, DC
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Combat and Operational Behavioral Health

INTRODUCTION

How should acute or chronic pain from combat 

and noncombat wounds and injuries be managed? 

What are the psychiatric implications of the control 

or elimination of the pain of injuries?1

 Which wounds 

cause the worst pain? Do the manifestations of pain in 

(or treatment strategies for) civilians differ from those 

for soldiers? Which emerging treatments can help? 

Are analgesic requirements met, or are they underestimated as in the past?2,3 Is drug-seeking behavior 

a contraindication to use of analgesics, or not? It is 

important to differentiate, with the patient’s help, pain 

resulting from injury, surgery, dressings, amputation, 

and physical therapy, as well as other types of pain 

associated with injury, illness, and emotional suffering. Pain caused by combat wounds and noncombat 

injuries in military personnel and in affected civilians 

are significant in the current context and may cause 

subsequent psychopathology.4–7 Consistent with the 

medical team approach, collaboration of surgeons, 

psychiatrists, anesthesiologists, and allied personnel 

is key to optimal management of pain due to wounds 

and injuries.

A primary task of medical personnel caring for the 

wounded, second only to assuring the safety of the 

patient and staff, is to relieve pain. Prompt, accurate 

diagnosis of mental disorders is key to the effective and 

safe relief of pain. Diagnosis of delirium,8 preexisting 

brain injury, substance abuse, psychosis, posttraumatic 

stress disorder (PTSD), Axis II disorder, or depression 

will affect measurement of pain, diagnostic procedures, precautions, and choice of analgesia. Failure to 

observe the lack of a pain response in a patient with 

a history of serious past trauma, or in a chemically 

paralyzed patient with the inability to communicate 

a pain response, or not diagnosing delirium, risk of 

violence, or high alcohol or drug levels, may cause 

preventable suffering or even death. 

Finding solutions to managing pain leads to central 

clinical and research questions in the care of injuries to 

patients of all ages. The answers have been modified 

or discovered in the last 25 years. Previous publications by the authors of this chapter have addressed 

posttraumatic psychological and neurobiological aspects of injury pain at different stages in the life cycle, 

and different stages postinjury.9–12 Pain is an essential 

focus of the requirements of the Joint Commission 

(formerly the Joint Commission on Accreditation of 

Healthcare Organizations), practice guidelines, treatment protocols, and continuing education. Prevention 

and relief of acute or chronic pain is more achievable 

as a result of treatment initiated at the scene of injury 

and continued throughout care. Pain relief for adults 

and children has a primary place in life-saving surgical care. Furthermore, it is important from a metabolic 

point of view because it decreases the stress response 

that activates the release of the catabolic hormones, 

catecholamines, and cortisol. Treatment to control 

metabolic and stress responses in burns, for example, 

has been tested to confirm a reduction in subsequent 

stress as outlined below.

Which wounds cause the worst pain? The patient 

is the judge of this, and will answer with self-report 

if asked, but may not volunteer this information, 

especially if stoical in temperament. Orthopaedic 

injuries including amputation may cause patients to 

rate pain “25” on a 0-to-10 scale, and the pain may 

rapidly recur with a delay in administering a dose of 

morphine. Burn patients frequently report their most 

severe pain being caused by dressing changes or from 

the donor sites for skin grafts. Although any bodily 

location—including internal organs—can be the site of 

severe pain, areas that are highly innervated, and thus 

most likely to be painful after wounds, are common 

locations of the most severe pain. These include parts 

of the face, scalp and neck, arms and hands, genitals 

and perianal area, and legs. Unexplained behavioral 

symptoms including confusion, combativeness, anger, 

emotional withdrawal, or anxiety may be secondary 

to an unrecognized wound, or a wound causing unrecognized pain.

There is growing evidence to indicate that successful 

pain relief appears to lessen posttraumatic stress, anxiety, and depression, although in one study, the N-methyl-d-aspartic acid (NMDA) antagonist ketamine, which 

is widely used in burn care, was shown to increase 

PTSD symptoms while protecting against posttraumatic reduction of hippocampal volume.13 That study 

is of 30 burned adults, 15 with and 15 without PTSD, 

and provides “evidence that smaller hippocampal size 

in trauma-exposed individuals is a result of traumatic 

stress.”13(p2194) Pain continues to be the subject of extensive research, and in hospital settings ongoing pain 

monitoring and team consultations for complex cases 

is the standard of care. Such teams include nurses, 

surgeons, anesthesiologists, psychiatrists, neurologists, 

pharmacists, physical therapists, ethicists, and others. 

Pain in those with injuries is the subject of great clinical 

attention, systematic evaluation, focused research, and 

a broad and growing range of pharmacological and 

psychological treatment options. Converging research 

in both genomics and neurobiology promises to offer 

new options to improve pain management for the 

injured patient in the future.

There is a well-established knowledge base with 
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Pain Management

which to design plans to manage and eliminate pain 

in injured children and adults.14,15 Making appropriate 

use of this knowledge is important for everyone caring for those in pain. The evaluation of children’s pain 

requires understanding their ways of communicating, stage of development, their mental impairments, 

and the emotional, as well as physical, effects of pain 

in selecting the appropriate treatments. Similarly, 

evaluation of adults’ pain requires listening to their 

complaints of pain and recognizing the unique needs 

of special populations, such as intensive care patients, 

those with mental or physical disability, substance 

abusers, and the elderly. 

Although psychological elements of treatment, 

such as preparation for painful procedures and hypnosis, are less likely to be covered by protocols than 

pharmacological approaches, they enable patients to 

lessen their own pain and are effective components 

of care.1,16–18 Psychological methods of pain relief do 

not have the risks of drug side effects, toxicity, or 

dependence but may be less effective than drugs. 

Systematic pharmacological research with severely 

injured patients has established the benefits of acute 

management with high-dose morphine and possibly 

benzodiazepines (although some literature indicates 

lorazepam may worsen outcomes),19 other analgesics, 

and adjuvants, utilizing intravenous and other routes 

of administration, mainly in ventilated patients. 

Further advances in management of injury pain are 

continuing. 

A large contribution to pain control for military 

wounded has been in the field of regional pain control. 

It is now possible for casualties of bullet or blast injuries to have at least one extremity rendered pain free 

by the ultrasound-guided placement of a nerve-block 

catheter and administration of appropriate anesthetic. 

These catheters may be maintained in place and connected to infusion pumps. This may allow the casualty 

to remain pain free during the first surgical interventions in theater, through the evacuation to Europe, 

and through washout and further debridement at 

Landstuhl Army Regional Hospital in Germany and 

across the Atlantic to military hospitals in the United 

States. It is anticipated that this will prove to be another 

contribution to a lower incidence of narcotic addiction 

and complex regional pain syndromes in casualties of 

the global war on terror. 

The two temporal components of pain due to acute 

injuries include acute and chronic pain, which are 

further classified. Acute pain, the principal subject of 

this chapter, includes both background pain and procedural pain. Acute pain may be worsened by anxiety, 

depression, sleep deprivation, and “regeneration of 

nerve endings (possible neuroma formation, known 

as postburn neuralgia).”20(p319) Chronic pain is usually 

present for months to years and may not be easily relieved. It may result from scarring, contractures, and 

injury to a bone or joint; from bone formation in soft 

tissues (heterotopic ossification)21,22; or injury to the 

peripheral nerves (neuropathic pain). Although this 

chapter is not comprehensive, it provides scientific 

background, case illustrations, clinical approaches, 

and pertinent references to assist in developing an 

optimal multidisciplinary plan for pain management 

of patients suffering from combat and noncombat 

injuries.

ANATOMY OF INJURY-RELATED PAIN

The anatomic location of pain is a sign of tissue 

injury, underlying infection, or systemic illness. The 

sensory detection of pain (nociception) and pain 

are not the same. Nociception is, according to Sherrington,23 the sensory detection of a noxious event of 

potentially harmful environmental stimulus. Pain, in 

contrast, involves sensory and cognitive components, 

and is defined by the International Association for the 

Study of Pain as “an unpleasant sensory and emotional 

experience associated with actual or potential tissue 

damage.”24 The anatomy of pain involves both central 

and peripheral nervous systems.25 Patients with larger 

injuries generally suffer more pain. Due to the involvement of both central and peripheral nervous systems, 

and afferent and efferent pathways, approaches to 

pain management are needed to address both central 

brain and spinal cord receptors and peripheral nerve 

receptors.

Injury-Related Pain Cases

Case Study 21-1: A 26-year-old Afghani civilian male 

was injured by enemy rocket fire, sustaining a gaping penetrating injury to his left knee. The patient was dragged by 

his comrades to an austere casualty collection point inside 

a secure bunker. He presented screaming and clutching his 

left knee. Primary survey revealed normal mentation and 

respiratory status. A rapid secondary survey revealed no 

other injuries.

The patient was clearly stirred by the visual appearance 

of his knee. He was given an 800-μg fentanyl transmucosal 

lozenge to suck on while his knee was rapidly immobilized 

and dressed and he was comforted by one of his battle 

buddies. By the time intravenous access was obtained (less 

than 5 min), his pain response had significantly improved. 

The simple act of immobilizing and dressing (and thereby 

concealing) his injury was the essential treatment for his 

pain. Thirty minutes after his initial assessment, he was 

titrated with small boluses of intravenous ketamine (0.25 mg/
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Combat and Operational Behavioral Health

kg) to a comfortably dissociated state, whereupon a gross 

decontamination of his wound with copious irrigation could 

be performed.

The patient’s pain was subsequently controlled with immobilization and intermittent use of self-administered transmucosal fentanyl during the next 8 hours until transport could be 

arranged. The profound effect of covering and immobilizing 

his wound significantly decreased his pain response.

Case Study 21-2: A 55-year-old Iraqi male sustained 

direct-fire injury to his left foot, ankle, and tibia. He was 

treated with a tourniquet for hemorrhage control in the field 

and was rapidly transported to a surgical element. He was 

otherwise uninjured and remained alert through his transport. 

The associated direct-fire injury to several key nerves limited 

his immediate pain response; pain control was achieved 

initially through immobilization and intermittent small doses 

of intravenous morphine.

The surgeon’s assessment was that the patient’s best option for a functional recovery in the current environment was 

through a below-the-knee amputation allowing for maximum 

stump length. As the patient was counseled (through an interpreter) as to the surgical options of either attempts at limb 

salvage (with tremendous potential for follow-up infection, 

difficult rehabilitation, and fusion with limited range of motion) 

or amputation, the patient’s “pain” became acutely worse. 

After confirming that there had been no change in the 

status of his injured extremity to account for the surprising 

increase in pain, the interpreter was asked to inquire from the 

patient what would alleviate his new increase in “pain.” Upon 

questioning, he made clear the overwhelming angst he felt 

at the recommendation to amputate his leg. His answer routinely was “Insha’Allah” (English translation “God willing” or 

“If it is God’s will”). The surgeon required a decision from the 

patient, but the patient was unable to make the decision. 

It became apparent that to treat the patient’s pain and to 

continue with any treatment regimen, the patient’s psychological pain needed to be addressed. Through the continued 

verbal analgesic work and religious discourse of the Muslim 

interpreter, the patient eventually became much less distraught and his pain improved markedly. The patient was 

subsequently able to make a decision.

This case demonstrates the multifactorial components 

of pain generation, even in relatively acute traumatic denervation, and how these factors can precipitate a clinically 

severe pain syndrome, which may be relieved by a culturally 

appropriate intervention in the patient’s own language.

Case Study 21-3: A 4-year-old girl was caught in a burning house, sustaining a 55% full-thickness flame burn and an 

inhalation injury. Immediately after rescue, she was intubated 

at the scene by responding medics because of respiratory distress. To facilitate intubation and ventilation during transport, 

she was chemically paralyzed with cisatracurium and sedated 

with approximately 0.05 mg/kg of midazolam and 0.05 mg/kg 

of morphine sulfate as single bolus doses. As a result of witnessing her injuries, her parents were severely traumatized, 

but reassured that she was receiving optimal care.

On arrival to the burn unit she was placed on continuous 

infusions of these same drugs, at 0.05 mg/kg/h each, and 

muscle relaxation was stopped to allow a more accurate assessment of comfort. Assessment after spontaneous reversal 

of neuromuscular blockade revealed a grimacing, writhing 

child in need of further analgesia and sedation. The morphine 

sulfate and midazolam infusions were increased, titrating to a 

Richmond Agitation-Sedation Score of -2.3 Over the following 

2 weeks, until she was extubated, background infusions of 

these agents were gradually increased, as tolerance developed, in response to continuous monitoring of the status 

of her comfort. During this time she needed several skin 

grafting operations, which are associated with substantial 

postoperative pain. At maximum, doses required to maintain 

appropriate comfort were 0.50 mg/kg/h of morphine sulfate 

and 0.40 mg/kg/h of midazolam.

Procedural pain and anticipatory anxiety were important 

issues for her because she required at least daily bedside 

procedures during this period of intubation. Sedation for these 

interventions (dressing changes, intravenous line placement, wound debridement) was provided by the addition of 

ketamine intravenous boluses at 1 mg/kg, repeated every 20 

minutes as needed. When she was awake, the continuous 

presence of her parents, their verbal explanations and reassurance, and their touching her also facilitated her coping 

with pain, fear, and hospitalization.

Donor site and skin graft healing were complete by 2 

weeks, coincident in improvement of the child’s inhalation 

injury. After extubation, the need for sedation was lessened 

by removal of the endotracheal tube and for analgesia by 

healing of wounds. Intravenous background infusions were 

reduced by 10% per day, alternating drug reductions every 

12 hours (eg, 0600 hours reduction in morphine and 1800 

hours reduction in midazolam). During this period, as her 

pain and anxiety lessened, her parents became less stressed 

and more effective in supporting her and participating in 

dressing changes.26

Case Study 21-4: An 18-year-old man was involved in a 

high-speed truck accident and trapped in the wreck, which 

then caught fire. He suffered fractures and deep burns to 

both legs, a 65% mixed second- and third-degree surface 

area burn, and a comminuted closed fracture of the right humerus. After extrication and transport, he was intubated and 

mechanically ventilated for 4 weeks. His comfort management plan included escalating infusions of morphine sulfate 

and midazolam, supplemented by intravenous boluses of 

propofol (2–3 mg/kg) for procedures. At day 10 he underwent 

tracheotomy, which reduced his requirement for intravenous sedation. He underwent excision and grafting of his 

wounds, but required bilateral below-the-knee amputations. 

On weaning his sedation he was transiently delirious, and 

then manifested intrusive recall of the accident contributing 

to flashbacks and insomnia, which were relieved by lorazepam. He was initially depressed in response to his massive 

injuries, but this lessened with supportive psychotherapy, 

acceptance by his friends, and messages of family support. 

In his recovery phase, he developed severe neuropathic 

phantom leg pain that interfered with his rehabilitation. This 

improved with gabapentin, allowing him to be successfully 

fitted with prosthetics. After 6 months he was able to discontinue the gabapentin.27
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BIOLOGY OF PAIN

the modification of pain transmission via inhibitory 

interneurons.

There are multiple projections from thalamic 

nuclei to the cortex, primarily somatic sensory and 

association cortex. Although at least two classes of 

somatosensory cortical neurons can be identified with 

respect to their receptive fields and source of thalamic 

input, nociceptive inputs do not map to the cortex as 

do tactile inputs. Further, lesions to the somatosensory cortex do not result in loss of pain, suggesting 

that parallel or distributed processing of nociception 

in the cortex is likely.28,29 Studies examining cortical 

activation following painful stimuli highlight the 

multiplicity of regions involved, including the contralateral prefrontal cortex, as well as the middle and 

inferior frontal gyrus (Brodmann areas 6, 8, 9, 44, and 

45).30,31

The intense barrage of incoming pain stimuli associated with a trauma results in a decrease in thresholds 

for subsequent excitation of spinal neurons, as well 

as a greater response to subsequent stimuli and an 

expansion of receptive fields.32All of these adaptive 

changes likely underlie the increased pain sensitivity, 

or hyperalgesia, that typically follows a significant 

burn or multiple traumas. Hyperalgesia has long been 

characterized as “primary” if limited to the area of 

injury or “secondary” if it extends to areas adjacent 

to the site of damage.33 Primary hyperalgesia appears 

to require sensitization of both peripheral nociceptors 

and spinal neurons, whereas secondary hyperalgesia 

seems to depend on sensitization of spinal neurons 

alone.34,35 Both types of increased pain sensitivity can 

occur immediately following injury, but secondary 

hyperalgesia may take hours before reaching its peak 

and is likely to resolve before primary hyperalgesia.30

Interestingly, experimental data suggest that chemosensitive nociceptors can be recruited to become 

mechanosensitive receptors following injury.31 This 

ability to recruit otherwise “silent” nociceptors may 

play a role in primary hyperalgesia following injury 

or inflammation.

Any form of major trauma, including burn injury, 

results in a local and systemic response that includes 

fever, anorexia, and pain in the injured (primary 

hyperalgesia) and uninjured areas. Until recently, as 

indicated in the previous paragraph, this sensation was 

thought to occur by transmission of nerve impulses 

from the injured region to the spinal cord and the 

brain.36 Other mechanisms, in addition to nerves, may 

play a role.37 Drugs that silence sensory nerves work 

well to relieve acute pain. When inflammation occurs, 

drugs for acute pain are less effective. Local inflammaThere are several important concepts relevant to 

pain mechanisms to consider: (a) pain receptors in the 

skin (nociceptors), (b) the opioid system, (c) increased 

pain sensitivity (hyperalgesia), and (d) the emerging 

role of the nonopiate pain adjuncts including inhibitors of the enzyme cyclooxygenase-2 (COX-2) and 

gabapentin. 

Pain associated with trauma including burn or 

other tissue injury is transmitted by peripheral nociceptors—the peripheral endings of primary sensory 

neurons whose cell bodies are in the dorsal root of 

the spinal cord and trigeminal ganglia. Unlike other 

sensory receptors in the skin, nociceptors are without 

specialized transducing structures and essentially 

exist as free nerve endings. Different classes of nociceptive fibers can be involved in the experience 

of pain. Thermal or mechanical nociceptors convey 

stimuli rapidly (up to 30 m/sec) via thinly myelinated, small-diameter fibers classified as “A” or “A 

delta.” Polymodal nociceptors are also activated by 

hot stimuli, but transmit impulses more slowly (up 

to 2 m/sec) along small-diameter unmyelinated “C” 

fibers. Both A delta and C fibers are widely distributed 

in skin and in deep tissues.12 Nociceptive fibers, both 

A and C, enter the dorsal horn of the spinal cord and 

split into ascending and descending branches. The 

fibers terminate primarily in lamina I and in lamina 

II, although some A-fiber afferents may terminate 

more deeply in lamina V. Within lamina I, different 

projection neurons process the incoming stimuli. 

“Nociceptive-specific” neurons are only excited by 

nociceptors, but “wide-dynamic-range” neurons 

receive their input from both nociceptors and other 

mechanoreceptors.

Several ascending pathways convey afferent stimuli to the brain. The spinothalamic tract originates in 

lamina I and laminae V–VII and is the major ascending pathway for nociceptive input. The nociceptivespecific and wide-dynamic-range projection neurons 

in this tract terminate in the contralateral thalamus, 

particularly ventrobasal and posterior thalamic nuclei. The spinoreticular tract originates in laminae VII 

and VIII and sends both ipsilateral and contralateral 

projections to the reticular formation and thalamus. 

The spinomesencephalic tract originates in laminae 

I and V, where it projects to the contralateral mesencephalic reticular formation, the periaqueductal gray, 

and other sites within the midbrain. The spinocervical 

tract, and even the dorsal column of the spinal cord, 

also can convey nociceptive stimuli. In addition, in 

the dorsal horn, A-B fibers conveying sensations 

such as vibration and light touch are involved in 
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Combat and Operational Behavioral Health

tion at the site of injury (eg, burn) causes a rapid and 

long-lasting increase in the proinflammatory-signaling 

molecule in the brain, especially interleukin-1β in the 

cerebral spinal fluid. Blockers of interleukin 1β (eg, 

COX-2 inhibitors) strongly inhibit the hypersensitivity to pain.36,37 Increased levels of interleukin-1β cause 

increased expression of COX-2 and prostaglandin E 

synthase, with a resultant increase in prostaglandin E2. 

Thus the use of COX-2 inhibitors currently available 

will not only have antiinflammatory and antipyretic 

effects but also have antihyperalgesic effects by acting at local and central sites. Among those available 

are celecoxib (Celebrex [Pfizer Inc, New York, NY), 

nimesulide (Mesulid [various manufacturers], and 

meloxicam (Mobic [Abbott Laboratories, Abbott Park, 

Ill]). Additionally, trauma/inflammation-induced upregulation of protein kinase Cδ (PKCδ) and NMDA in 

the spinal neurons may also play a role in the hyperalgesia and mechanical allodynic.38 A growing body of 

evidence supports the notion that the upregulation of 

protein kinase Cα (PKCα) and NMDA are implicated 

in the mechanisms of chronic nociception.38 Hence the 

rationale for use of drugs such as ketamine, an NMDA 

antagonist.

PRINCIPLES OF PAIN THERAPY

Laboratory research is clarifying the synthetic 

and degradative pathways by which the levels of 

endogenous opioids are maintained in the body.39,40

In addition to the clarification of the dynorphin gene, 

the neural systems involved in pain and anxiety have 

been located. The three classes of endogenous opioid 

peptides are: (1) endorphin, (2) met-leu-enkephalin, 

and (3) dynorphin. Additional transmitters modulating pain include the monoamine (dopamine, norepinephrine, and serotonin) systems, substance P, and 

the g-aminobutyric acid system—each with its own 

specific brain receptor sites. Clinically, opioids are 

the first-line drug used to treat pain associated with 

injury. Selection of analgesics such as nonsteroidal 

antiinflammatory drugs (NSAIDs), COX-2 inhibitors, 

benzodiazepines, anticonvulsants, and adjuvants 

(eg, stimulants, tricyclic or serotonergic antidepressants, neuroleptics) may be made to modulate and 

potentiate the effects of narcotics. However, the analgesic effects of opioids are unpredictable, particularly 

under chronic pain conditions. This is partly due 

to downregulation of opioid receptors,37 and to the 

development of a condition called opioid-induced 

hyperalgesia (OIH).

Recent observations suggest that chronic administration of opioids leads to OIH. Thus, treatment 

with opioids is a double-edged sword; the treatment 

of pain may lead to a hyperalgesic state. OIH can 

occur during maintenance therapy, withdrawal, or 

both. OIH has been studied in three different clinical 

settings: (1) in former opioid addicts on methadone 

therapy, (2) in patients treated with opioids, and 

(3) in human volunteers. OIH can occur following 

both low-dose and high-dose opiate therapy.41–43

Mechanisms involved in OIH include sensitization 

of peripheral nerve endings, enhanced facilitation of 

the nociceptive signal transduction, altered kinetics of 

nociceptive transmitters, and increased sensitization 

of the second-order neurons to neurotransmitters.41,43

Excitatory amino acids (glutamate), NMDA receptors, 

and PKC seem to play a role in the development of 

OIH. The greater the opioid therapy, the greater the 

OIH will be. 

Tolerance to opioids can also occur acutely44; this 

emphasizes the importance of alternative or adjunct 

therapy with opioids for treatment of pain. Strategies 

to treat tolerance and OIH can include rotation from 

phenanthrene (morphine) to a piperidine (fentanyl) 

opioid derivative. The administration of NMDA 

antagonists (ketamine) prevents opioid-induced 

hyperalgesia and also overcomes tolerance.45 Dexmedetomidine, an α2

 agonist more potent than clonidine, 

has analgesic/sedative effects, particularly in combination with other drugs, and may reduce the incidence 

of delirium and other complications of withdrawal 

from opiates.46–49

Experience gained from treating other pain-associated conditions such as cancer, herpes, diabetic 

neuropathy, and degenerative diseases can also be 

applied to posttraumatic pain syndromes.50 The 

available therapies shown to be effective include 

anticonvulsant drugs, tricyclic and other antidepressants (duloxetine, venlafaxine), topical lidocaine, 

and tramadol. Of great recent interest is gabapentin. 

The mechanism of its action is unclear, but its effects 

on the α2δ calcium-channel subunit may result in 

decreased release of the neurotransmitter and suppression of central sensitization.51 The combination 

therapy of gabapentin with morphine resulted in 

greater reduction of pain than did either drug alone 

or placebo. The combination also had beneficial effects on pain-related interference with daily activities, 

mood, and quality of life.51 Combination therapies 

have the potential to simultaneously alleviate pain, 

insomnia, and mood instability or depression. Tolerance will most likely develop to this combination 

based on previous reports on receptor behavior and 

neuroplasticity.
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Pain Management

ADVERSE EFFECTS OF PAIN

Many factors contribute adverse physiological, behavioral, and psychological effects to the experience 

of pain and injuries.52 It is often difficult to differentiate the specific contribution of pain to the range of 

psychological problems that develop following injury. 

The injury itself may or may not be unexpected and 

normally initiates an ongoing experience of severe 

pain. Shortly after the injury, these patients often find 

themselves in an emergency setting where they may 

undergo application of wound dressings and possibly 

extensive surgery. Hospitalization involves separation 

from the military component and friends, who themselves may have been injured or killed. Treatment usually includes painful dressing changes and support for 

adjustment to permanent and emotionally traumatic 

changes in their bodies’ appearance and function. The 

traumatic nature of severe injuries is compounded by 

the fact that some are inflicted in battle, while others 

are due to mistakes, accidents, or intoxication, or are 

intentionally inflicted or self-inflicted. Injured patients 

frequently manifest severe psychological reactions 

such as nightmares, flashbacks, acute sadness and 

grief, irritability or anger, and behavioral regression.11,53

For example, the psychological intensity of burn trauma, and particularly the relentless stress of extended 

hospital treatment for a burn, has been compared to 

“inescapable shock” or “learned helplessness,”54 both 

of which are models for PTSD.55,56

About one third to one half of injured people eventually develop PTSD,and over half display significant posttraumatic stress symptoms.57 PTSD and posttraumatic 

stress symptoms are reactions to diverse traumatic events 

related to combat and civilian injuries, assaults, witnessing 

violence, disasters, medical illness, physical and sexual 

abuse, and other psychological traumas not involving 

injury.58,59 Symptoms of this disorder include increased 

intrusive recollections, numbing and avoidance, and 

hyperarousal.60 The manifestation of these symptoms is 

triggered by environmental factors, such as exposure to 

objects, people, or situations reminiscent of the trauma. 

PTSD occurs when symptoms are experienced for most 

days and interfere in either a social or occupational setting. 

PTSD causes significant difficulties for a person’s social, 

educational, occupational, biological, and life-cycle development. Children with PTSD are often so preoccupied 

with intrusive recollections or are so hyperaroused that 

they have difficulty processing social information.61,62

The intrusion of trauma-related memories and extreme levels of arousal that traumatized individuals 

experience interfere with job performance and learning at school. Traumatized people often avoid social 

situations secondary to fear and anxiety that memories 

will reoccur. Patients with injuries also develop mood 

(especially depressive), anxiety, sleep, sexual, behavioral, elimination, and attentional problems. PTSD 

symptoms cause tremendous morbidity and may 

persist for many years. Evidence indicates that once 

posttraumatic symptoms become persistent, they are 

refractory to treatment.63 Accordingly, it is important 

in each case of a person sustaining an injury to seek 

interventions that may prevent or ameliorate the 

development of PTSD. Evidence is slowly accumulating suggesting that the early postinjury preventive 

or therapeutic administration of cognitive behavior 

therapy, or of drugs (eg, morphine, propranolol, serotonin reuptake inhibitors, or tricyclic antidepressants) 

can block the emergence of PTSD symptoms in some 

cases, including combat injuries.64–68 

GENETICS

This section briefly outlines the genetics of pain, the 

genetics of opiate drug responses, and the important 

genetic determinants of racial differences in response 

to pain or its treatment. The human genome project 

has revealed data on genomic variations that may 

influence pathologic states, and are certain to influence treatment advances in the future. Nevertheless, 

the molecular biology and genetics of pain has lagged 

behind the research in diseases such as hereditary, 

cardiovascular, and oncologic disorders. Reports 

continue to emanate, however, on the genetic factors 

influencing nociceptive sensitivity and responses to 

drugs. Genes involved in pain perception, pain processing, and pain management include opioid receptors, transporters, NMDA receptors, α2A adrenoceptors, 

and more recently discovered, guanine triphosphate 

cyclohydrolase—the rate-limiting enzyme for tetrahydrobiopterin synthesis, a key modulator of peripheral 

neuropathic and inflammatory pain.69,70

Pain is a complex trait with interaction of multiple 

genes, each with varying effect, that together with 

environmental and cultural factors, play a role in 

sensation of pain. Altered sensitivity to pain can be 

due to hereditary disorders; usually these are due to 

homozygous disorders. For example, a mutation in 

nerve growth factor has been found and in this instance 

there was complete absence of pain.71 Recently, a “pain 

protective haplotype,” the guanine triphosphate gene, 

has been identified with allelic frequency of 15%.72 This 

haplotype was associated with decreased pain sensitiv-
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ity in low-back-pain patients following herniated disc 

surgery and in volunteers undergoing experimental 

pain.70 The degree of activity or inactivity of enzymes 

that metabolize drugs may also influence drug efficacy. 

It is well established that polymorphisms of the cytochrome P-450 (CYP2D6) enzymes influence analgesic 

efficacy of codeine, tramadol, and tricyclic antidepressants.69 Similarly, blood levels of some NSAIDS are 

dependent on CYP2C9 activity.

Catechol-o-methyltransferase is a key regulator 

of pain perception, cognitive function, and affective 

mood. Polymorphisms in this enzyme and μ-opioid 

receptors are known modulators of pain sensitivity and 

opioid efficacy.73,74 In addition to endogenous factors 

that alter pain sensitivity, exogenously administered 

small molecules (peptides) that can alter gene activity 

have been shown to influence pain response. Progress 

in molecular biology has enabled gene expression 

modulation (in animal models) using “knock outs” 

or antisense ribonucleic acid (RNAi) and small RNA 

molecules (sRNA). Gene therapy for patients with 

chronic pain shows encouraging results. Additional 

studies that have been performed on candidate genes 

transmitting pain include opioid receptors, transporters, and other targets of pharmacotherapy. Future 

studies should also elucidate the side-effect profiles 

of these gene manipulations. The challenge is to deliver this RNAi or sRNAs to target tissues such as the 

central nervous system. Genes can also affect signaling pathways related to pain sensitivity and clinical 

response.7,74 Future studies could characterize the roles 

of different genes and metabolizing enzymes along 

with demographic and clinical variables that may 

influence treatment of pain both in acute and chronic 

situations.75 

Few studies of pain in humans have described the 

ethnic or racial background of their subjects. In spite of 

this limitation, findings from any given study are then 

generalized to other ethnic and social groups, although 

there is no evidence base for such generalization of the 

results of these studies. Therefore, genetic studies of 

varying ethnic and social groups are indicated. The importance of genetic factors controlling drug disposition 

and response has received increased attention.76 For example, the variability of a single drug, midazolam, was 

11-fold.77 Selective sequencing of CYP3A4 and CYP3A5 

genes revealed 18 single-nucleotide polymorphisms 

(SNPs), including eight novel CYP3A4 SNPs. These 

differences may or may not account for such variability. Thus, the so-called standard doses of a drug may 

have toxic effects in some but fail to produce expected 

effect in others. Racial and ethnic differences have been 

described for a range of drugs and reflect genetic, environmental (cultural and dietary), and pathogenetic 

causes. Polymorphism of drug-metabolizing enzymes 

(eg, CYP2D6 of the cytochrome P-450 system) is well 

recognized and can affect drug therapy, such that lower 

or higher drug doses should be used. Thus, differences 

in response to pain treatment can be due to pharmacokinetic, pharmacodynamic, or pharmacogenetic factors. 

The identification of such genetic differences will result 

in better therapeutics. The role of pharmacogenetics 

can also be confounded by injury-induced alterations 

in drug metabolism.78

METHODS OF PAIN ASSESSMENT

The perception of pain is subjective and poses 

unique challenges for its objective assessment. The 

measurement of pain has developed to assess both 

the self-report of pain experience and behavioral 

observations. Behavioral measurements can lead to 

data correlating behaviors to subjective reports of 

pain. Self-report measures are used for patients over 

4 years of age, and require sufficient cognitive and 

language abilities. Psychiatric disorders may indicate 

an increased requirement for analgesia. For example, 

a severely injured woman with borderline personality disorder who complained constantly of pain was 

later shown to have had negligible levels of endorphins. Alternatively, patients with Axis II psychiatric 

disorders may exaggerate their needs for analgesia 

and need psychiatric or substance abuse evaluation, 

especially in later stages of care when their wounds are 

largely healed. Other patients, such as those suffering 

depression or bipolar disorder, once treated with antidepressants or mood stabilizers may have significantly 

reduced pain. Patients with factitious disorders may 

use pain or self-inflicted injuries to obtain opiates. 

Patients with a brain injury, delirium, or limited cognitive and language skills may not be able to accurately 

complete self-report measures of pain. 

Various methods assess pain in children.79 Surveys 

of pediatric anesthesiologists have reported that the 

infant’s respiratory rate is commonly used as an indicator of pain.80 Other useful behavioral indices in young 

children include facial expression,81 body movement 

(particularly limb withdrawal to painful signals82),

and crying. Psychophysiological indices include blood 

pressure, pulse, respiratory rate, and neurochemical 

activity.82 There are combined behavioral and psychophysiological indices (eg, the COMFORT scale,83

which is composed of six behavioral dimensions 

[alertness, calmness, muscle tone, movement, facial 

tension, and respiratory response] and two physiologi-
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Pain Management

cal dimensions [heart rate and mean arterial pressure]) 

to assess postoperative pain. Using this scale, it was 

found that the most accurate variables for measuring 

pain were behavioral activity, mean arterial pressure, and heart rate.84 Methods in older patients take 

advantage of the ability to self-report symptoms and 

experiences. The Poker Chip Tool85 allows children 

ages 4 to 8 to describe their pain as “pieces of hurt,” 

using one to four poker chips. The Faces Scale86 asks 

children to choose a picture of a face with expressions 

of various gradations of pain, rated 0 to 5, from “no 

pain” to “the worst pain.”

The most practical and standard pain assessment 

tools in adolescents and adults are verbal or visual (or 

both) analogue scales, asking patients to rate their pain 

on a continuum of intensity along a line using numerical anchors, commonly from 0 to 10, from “no pain” 

to “the worst pain.”87 Visual analogue scales, the most 

commonly used instruments, have good psychometric 

properties and are easily administered. The numerical 

anchors have been enhanced in the visual analogue 

instruments by adding colors to the intensity ratings.75

Pain diaries are also useful, and require the repeated 

numerical rating of pain over the course of time along 

with other relevant information such as activities, 

stressors, or alleviation with medications. 

Comfort management will have different priorities 

depending on the locale of care: prehospital, inpatient, 

and outpatient. In the prehospital setting, the priority 

must be safe and efficient care. The airway must be 

secured. The patient must cooperate with evaluation 

and transport. Medication policies should be simple 

and follow trained protocols. These protocols generally rely on intravenous opiate and benzodiazepine 

dosing, and may include drugs to facilitate endotracheal intubation, including neuromuscular blocking 

agents.88

In the inpatient setting, the focus is on continuous 

evaluation and titration of sedatives and analgesics. Inpatient protocols may be more complex, and 

importantly include regular objective evaluations 

of pain and anxiety using one or more of several 

available scales.89,90 Inpatients may also benefit from 

patient-controlled analgesia devices, which have been 

shown to be associated with reduced total opiate requirements.91 Peripheral nerve blocks92 or continuous 

epidural anesthesia are an excellent adjunct in some 

patients, particularly in the management of short-term 

or postoperative lower body pain.93

In the outpatient setting, where monitoring is less 

feasible, patient safety is an added important consideration. A differentiation should be made between neuropathic pain (eg, phantom pain) and more standard pain 

(eg, open wounds). The former is ideally addressed 

with nonopiate medication or alternative therapies to 

avoid the specter of opiate dependence.94 

METHODS OF PAIN MANAGEMENT: OVERVIEW

Until 20 years ago, pain management for acutely injured patients was relatively neglected due to concerns 

about respiratory depression and its effect on survival. 

Pain became recognized as critically undertreated, 

increasing physiological stress and adversely affecting 

outcomes. Improved pain relief became a priority and 

was successfully addressed by increased use of opiates, 

benzodiazepines, other analgesics, and anxiolytics. 

Today, in managing the pain of severely injured patients with intractable pain and anxiety, combinations 

of agents are commonly used, with close monitoring 

of vital signs and symptoms. Among these agents are 

high-dose opiates and benzodiazepines, NSAIDs, and 

the judicious use of both atypical and typical antipsychotics, antiepileptic drugs, and antidepressants. 

Signs of physiological dependence such as increased 

pulse, blood pressure, or insomnia are common upon 

tapering sedatives after prolonged administration but 

do not indicate psychological addiction; these signs are 

managed by adjusting the weaning regimen. 

Pharmacological approaches are the first-line treatment in management of pain due to combat or noncombat injuries. In addition, psychological methods 

are essential in conjunction with drugs, and their effectiveness is also well established. These include psychoeducation, psychological preparation for procedures, 

relaxation techniques, hypnosis and self-hypnosis, 

guided imagery, and therapeutic touch. Psychological 

approaches enhance trust and communication with the 

patient, facilitating hope, positive coping, and optimal 

recovery despite potentially stigmatizing disfigurement and functional losses. 

PHARMACOLOGICAL MANAGEMENT OF ACUTE PAIN

Two key principles in acute management of pain 

include frequent reassessment and dose titration. It is 

not possible to predict with accuracy the medication requirements of an individual patient. These will vary with 

pain intensity, anxiety state, personality characteristics, 

and distractions. Frequent reassessment of the efficacy of 

pain and anxiety control is essential. Ideally, these findings are documented so that pain and anxiety control can 
348

Combat and Operational Behavioral Health

smoothly transition between shifts of caregivers. There 

are several acceptable scales that are validated for this 

purpose.95 Analgesic and anxiolytic doses will need to be 

titrated to the findings from these reassessments. 

Ideally, every patient care unit will have specific 

written guidelines describing the preferred methods of 

pharmacological pain management. These guidelines 

should have a limited formulary to facilitate development of a working knowledge of drugs used by all 

staff, and allow for bedside dose-ranging depending 

on the findings at regular reassessment. 

There are a limited number of drug classes used 

in acute comfort management. The cornerstones are 

opiates and benzodiazepines. Opiates are potent analgesics with some sedative properties. Although they 

are very effective, side effects are common and include 

respiratory depression and ileus. Benzodiazepines 

are potent anxiolytics. The synergy between these 

two classes of drugs is strong.96 Other drugs useful in 

this setting are propofol (a short-acting intravenous 

anesthetic), ketamine (an intravenous dissociative 

agent), haloperidol (an intravenous antipsychotic), 

and dexmedetomidine (a centrally acting α2 agonist). 

A complete program of pain and anxiety management 

in the intensive care unit is beyond the scope of this 

chapter, but the reader is referred to many excellent 

reviews.97 The important point is that acute pain and 

anxiety management will have an important effect 

on subsequent incidence and severity of acute and 

posttraumatic stress symptoms.65 Frequent pain and 

anxiety assessment should be a regular part of care of 

all acutely injured patients.

PSYCHOLOGICAL MANAGEMENT OF PAIN AND GRIEF

Psychological strategies are quite effective for 

pain1 and for associated anxiety and grief. Reassurance, supportive interventions, increasing structure, 

and a variety of psychosocial interventions geared to 

the patient’s interests can be extraordinarily helpful 

in relieving pain, anxiety, and the sense of helplessness. Videos, television, hypnosis,18 guided imagery, 

relaxation, virtual-reality methods, and therapeutic 

touch may also effectively relieve pain and discomfort. They should be individualized, because some 

methods are more acceptable for one individual than 

for another; they are well established as key interventions for pain relief, with a very low risk of adverse or 

toxic effects. Psychological management of the patient 

and interventions also include assessment for safety, 

empathic listening, modifying cognitive distortions 

through cognitive behavior therapy, providing hope, 

and facilitating a positive long-term attitude toward 

recovery. 

Regarding pain-associated sadness and grief, 

psychotherapeutic approaches should respond to 

the phase of grief (including grieving their injury) 

the patients are in, and their phase of recovery from 

injury. Such grief exacerbates pain, and may be triggered by loss of a close buddy, seeing children die, 

mass casualties, or terrorist attacks. Some bereaved 

patients will have prolonged grief disorder, newly 

proposed for DSM-V.98 Prolonged grief disorder is 

distinguished from bereavement by causing impairment for at least 6 months with one of these three 

symptoms in criterion B, which is called “separation 

distress”:

1. intrusive thoughts related to the deceased, 

2. intense pangs of separation distress, and 

3. distressingly strong yearnings for that which 

was lost. 

These symptoms must occur daily or to an intense 

or disruptive degree. In addition, five of the following 

nine symptoms of criterion C, “cognitive, emotional, 

and behavioral symptoms,” must be present daily or 

to an intense or disruptive degree: 

1. confusion about one’s role in life or diminished sense of self; 

2. difficulty accepting the loss; 

3. avoidance of reminders of the reality of the 

loss;

4. inability to trust others since the loss; 

5. bitterness or anger related to the loss; 

6. difficulty moving on with life; 

7. numbness (absence of emotion) since the loss;

8. feeling that life is unfulfilling, empty, and 

meaningless since the loss; and 

9. feeling stunned, dazed or shocked by the 

loss.

The duration must be at least 6 months from the 

onset of separation distress; it must cause clinically 

significant distress or impairment in social, occupational or other important areas of functioning; and 

lastly, it cannot be due to a substance, general medical 

condition, or other disorder. When present, family support is key to relieving pain, anxiety, and grief. Family 

understanding, coping, resilience, and capacity to 

support need to be assessed and reinforced. Provision 

of supports, including counseling and psychotropic 

medications where indicated, facilitates the capacity 

to care for the patient. 
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Pain Management

SPECIAL PROBLEMS

Ventilated Patient

Analgesia and sedation in the mechanically ventilated patient has the added factor of maintaining 

airway security and patient safety. The agitated patient will not only suffer emotionally, but may die if 

the endotracheal tube or vascular access devices are 

dislodged.99 A “lightly asleep but arousable” state, or 

a Richmond Agitation-Sedation Score of -2, is a common objective when caring for intubated patients in 

the intensive care unit.

Burns and Multiple Traumas

Patients with burns and multiple traumas will have 

very large amounts of noxious stimulation associated 

with wounds and their management. The level of 

analgesic required can have adverse effects on respiratory and hemodynamic status. At times, these adverse 

effects must be accepted and managed (via mechanical 

ventilatory or vasopressor support or both) to ensure 

adequate patient comfort and safety. It is important 

that other potential causes of these problems (most 

commonly sepsis) be excluded.

Amputation Pain

Amputated limbs are a common cause of acute and 

chronic pain syndromes. It is important to distinguish 

acute surgical pain (eg, bone and soft-tissue pain) 

from neuropathic pain (eg, phantom pain), as pharmacological and nonpharmacological management 

strategies differ.100

Weaning

Most pain and anxiety medications stimulate receptor changes that mandate weaning if consequences 

of abrupt withdrawal are to be avoided.101 Opiate 

withdrawal will cause tremulousness, autonomic 

hyperactivity, diarrhea, and emesis. Benzodiazepine 

withdrawal can result in seizures. Gradual weaning is 

well tolerated, with low rates of withdrawal symptoms 

or drug dependence, even when very high drug doses 

are used acutely.102

Pediatric Pain 

Pain in children is treated according to similar principles to those outlined in this chapter, but with specific 

changes adapted to the pediatric population for body 

weight, any pediatric illnesses, developmental status, 

and dependency on parents and family.10 Dosages 

are calculated on a milligram per kilogram basis, and 

treatment is modified if there is concomitant pediatric 

illness. The developmental status of the child—infant, 

toddler, school age, and adolescent—requires adaptation to the physical, mental, emotional, and relationship characteristics of those stages. 

Psychiatric Risk Factors

The principal risk factors for pain complications 

include inadequate analgesia, delirium, unrecognized 

infection or injury, sleep disorders, preexisting psychopathology, self-inflicted injuries, prior addiction, PTSD 

or other anxiety disorder, emergent depression, somatoform disorders, and factitious disorder. Diagnosis 

and specific treatment of these conditions or disorders 

is essential to effectively manage the associated pain. 

Not all apparently psychological contributions to pain 

are that, and further diagnostic investigation is often 

warranted.

Pain Management and the Issue of Addiction

Prior addiction to or abuse of alcohol or other 

substances is very commonly associated with noncombat injuries, as is withdrawal from the drug of 

abuse, especially alcohol, during acute treatment of 

the injuries. As a result, treatment of all injuries should 

include a careful history of substance abuse, toxicology 

screening, ongoing evaluation of possible withdrawal, 

treatment of withdrawal symptoms, and interventions 

to reduce the risk of continuing addictive behavior 

posttreatment.103

The Ethics of Pain Control

Pain control may become complicated. As noted 

above, inadequate relief of pain results in increased 

risk for adverse psychiatric sequelae and poorer 

outcomes. There is therefore an ethical obligation to 

relieve pain to reduce the likelihood of harm. Acutely, 

treatment of serious pain is occasionally complicated 

by excess sedation, respiratory depression, or hypotension. Over the longer term with chronic pain 

management, drug dependency can occur, particularly 

in patients who have been substance abusers. If, in the 

management of chronic pain, overuse of pain medication occurs or is perceived, serious medical com-
350

Combat and Operational Behavioral Health

plications may arise and could result in challenging 

medicolegal consequences. It is an ethical imperative 

that such risks, as well as those of undertreatment, 

are acknowledged, considered, and appropriately 

managed in formulating a sound treatment plan for 

the injured patient.104–106 

SUMMARY

The objective of this chapter is to aid in improving 

management of acute or chronic pain from combat 

and noncombat wounds. It addresses the psychiatric implications of the control or elimination of 

injury pain, the wounds causing the worst pain, and 

differences in treating soldiers from civilians. Four 

case examples (of patients aged 4, 18, 26, and 55) 

that were presented with combat and noncombat 

injuries provide practical illustrations of the range 

of approaches to pain problems needing evaluation 

and treatment. Biological factors are presented that 

affect pain, including anatomic, genetic, and pharmacological considerations. A range of established 

and emerging treatments is described, and ways to 

assess whether or not analgesic requirements are 

met, underestimated, or exceeded are detailed. The 

problem of addictive behavior in the military must be 

considered both acutely, and later in care, but is not 

a contraindication to providing adequate pain relief. 

Approaches to pain from injury, surgery, dressings, 

amputation, and emotional causes are discussed. 

Pain caused by wounds and other injuries in military 

personnel and civilians is significant, and may trigger 

subsequent PTSD, depression, or behaviors associated 

with disability, especially in vulnerable individuals. 

Consistent with the medical team approach, as well 

as the authorship of this chapter, multidisciplinary 

collaboration of psychiatrists, surgeons, anesthesiologists, and allied personnel is key to optimal pain 

management.

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