Use and Safety of Ketamine: In Plain Terms

A Bad Reputation

Not surprisingly, a number of you have voiced your concern about our intention to conduct a study in which ketamine, a drug known to be abused recreationally and commonly used by veterinarians, will be trialed in children.

However, the current use, safety and benefits of ketamine are much greater than you might suspect. Back in the 70’s, when the drug was first used for sedation, it very quickly developed a bad rap in this country. This was probably due to the fact that when coming out of sedation, some people experienced psychotomimetic effects such as a sense of intoxication, slowing-down, relaxation, out-of-body floating, psychedelic colors or lights, faceless people, going places, etc.[i]. Since this drug is chemically related to drugs like PCP, these side-effects caused it to quickly fall out of favor[ii].

Wide Use of Ketamine

For sedation of both children and adults, ketamine is perhaps the most widely used agent in the world. In addition to its sedation effectiveness, ketamine has some unique safety features. It does not depress the respiratory system as do regular anesthetics[iii]. Therefore, breathing apparatus is not necessary and the patient is at less risk. Additionally, once administration of the drug has stopped, its effects are very short lived. In all but a few cases[iv] out of the many hundreds of thousands1 in which ketamine has been used, both its disorienting and sedating effects have been transient and typically resolve within 30-120 minutes1. A study which included over 11,000 administrations of ketamine to children concluded that it has a wide margin of safety when used within administration standards[v].

In all recorded instances of accidental overdose, with the exception of one critically ill infant, all patients were normal on recovery and experienced no related consequences; even the 3 year boy who received 100x the intended amount[vi]. For comparison sake, a lethal dose of iv ketamine requires 400mg/kg[vii], a sedation dose of ketamine delivered through a nasal spray is approximately 3mg/kg[viii]. In our study, we intend to administer around between 1 and 2mg/kg.

These characteristics have made ketamine an ideal agent on the battlefield as well as in countries in which sophisticated hospital support is not available. Ketamine is a core medicine in the World Health Organization’s “Essential Drugs List” and is a standard technique for the American Red Cross[ix].

While the use of ketamine in this country is significantly less than elsewhere, it is nevertheless used for the following:

• pediatric sedation in dentistry and emergency rooms
• as an analgesic (pain reducer) for both acute and breakthrough chronic pain
• as a bronchodilator
• as a neuronal protective agent in prolonged seizures

Side Effects from Low-Dose Ketamine

So what about those “psychedelic-like” emergence experiences that caused so much concern? They probably derive from the fact that, rather than affect the whole brain as regular anesthesia does, ketamine works by disconnecting the central nervous system from the perception of external stimuli[x]. It has been suggested that the disorienting sensory experience occurs due to the expected and harmless reestablishment of that connection1.

Studies in which people were asked to describe their experience revealed that most of them did not find the experience unpleasant[xi]. Further, studies report that children are less concerned about these experiences than adults. This could be due to the fact that their developmental world still contains unclear boundaries between reality and fantasy[xii]. The effect is known to disappear within 2 hours.

The other symptoms associated with ketamine are fairly harmless, especially when compared to the drug’s usefulness. They include nausea, vomiting, dizziness, fatigue, blurred vision, itching, emesis (uncontrolled urination) and, as yet unreported, a cooling sensation. When used at a sedation dose, mild respiratory anomalies may occur, however these anomalies are not of clinical importance and most of them resolve without assistance[xiii].

Finally, some degree of tolerance to the drug has been observed[xiv]. This would necessitate one to increase the dose to achieve the same effect. However, this phenomenon has not been observed over the 2+ years that it has been administered to children in our pilot study. Finally, while ketamine belongs to the same class of drugs that includes PCP, ketamine does not create a physical addiction[xv].

Why Do We Want to Use Ketamine?

We hope that we have allayed some of your concerns about the safety of ketamine…particularly when it comes to children. But you are probably still wondering why we want to use it as our goal is not to sedate children.

Recently, there has been a growing interest in ketamine as a rapid and effective treatment for people with depression and bipolar disorder who are resistant to other treatments. Since 2008 we have conducted a pilot study in which we have used doses similar to those that will be given in the clinical study. We selected ketamine because it is known to reduce core body temperature and to decrease fear sensitivity: two important characteristics of Fear of Harm (FOH).

As of Dec. 2012, 60 patients (primarily children but also teens and young adults) who are characterized by FOH, and who have not responded to currently available treatments, have participated in it. All but three of the pilot study subjects experienced a remarkable reduction, and even resolution, of all the symptoms directly related to this pathway. This is not to say that there are not psychological and developmental challenges left behind that need to be addressed. But at least the neurological barrier has been lessened or removed, allowing them to work on those areas. As for psychotomimetic and other side effects, all of the pilot study participants experienced some degree of them. But for all of the participants the effects resolved within 45 minutes. Further, as each person’s treatment has continued, side effects have decreased. Read more about the Pilot Study.

In addition to our work, similar thinking has led others to conduct studies in adults with treatment resistant depression and bipolar disorder. Some of these studies preceded ours and others were concurrent. While they have used different methods to administer the ketamine, they too have arrived at similar conclusions: that ketamine provides a rapid and sustained abolition of symptoms in a large percentage of study patients who were formerly unable to find relief[xvi].

The means by which ketamine is effective for people with depression and bipolar disorder is not well understood. However, it may be due to a shift of balance in the activity between receptors on neurons (the message sending cells in your brain) that promote cell growth and receptors on neurons that shut down cell growth. Surprisingly, both of the receptors are the same type. They are called NMDA receptors. But because they are located on different parts of the cell, they have different jobs. In conditions like bipolar disorder and depression, the growth-interrupting receptors may be chronically over-activated. A line of thinking is that when a very low dose of ketamine is given, it blocks just enough of the ‘bad’ receptors while allowing most of the ‘good’ receptors to keep working. It even causes a situation in which the ‘good’ receptors can receive increased signaling[xvii]. The beneficial response is almost immediate and, through a microscope, new connections and stronger cells can be seen within hours.[xviii]

NMDA receptors are important to that pathway in the brain that we have identified as being associated with the broad range of FOH symptoms and which we believe is dysregulated. When ketamine positively affects the neurons in that pathway, all of the many downstream behaviors and symptoms associated with the pathway improve.

We also want to let you know that when ketamine is administered in very high doses, or when given in fairly high doses during a period known as the brain growth spurt, it is known to destroy neurons in an irreversible manner. Importantly however, it was also found that after the brain growth spurt, a distinct developmental period that ends at 3.5 yrs, and at doses even 100 times that which we will be using, this cell death does not occur. If you are concerned about this information, more can be found here. (all supporting citations found in links)

Given that disorders such as depression, anxiety and bipolar disorder cause a person’s neurons to lose strength and connectivity, and that low doses of ketamine improve those losses, an argument could be made that the risk of neuron degeneration is much stronger without ketamine than with it.

There is much work to be done. The study that we are about to start will provide a substantial boost to that work. In addition to measuring the effects of ketamine on this population of children, we will also gather a variety of other biological information that will contribute to future studies.

Safeguarding the Children in Our Study

The safety and well being of children is always at the forefront of our thinking. It is why we do what we do. We have demonstrated to the Federal Drug Administration that our proposed study insures that safety. Some of the ways that we will do this include the following.

• We have chosen to err on the side of safety by using more stringent exclusion guidelines than our purposes require.
• Among other things, a normal EKG and annual physical within 3 months prior to participation are required for inclusion
• Vital signs of all participants will be frequently monitored by a nurse practitioner at each and every drug administration.
• The nurse practitioner will stay with the participant, in his or her home, for the hour prior to, and at least two hours post, each administration: the time required for the normal resolution of initial drug effect.
• As mentioned above, the dose of ketamine administered falls well within studied safety ranges. The maximum dose that any child will receive is 3mg/kg.
• If a child and/or parent decide that they would like to leave the study, they may do so at any time for any reason.

At this time, participants of our study are limited to the metropolitan area. Subjects must be between the ages of 6 and 12 and weigh between 44 and 220 lbs. If you live in this area and would like to find out more about it, please contact our Director, Alissa Bronsteen. She can be reached atabronsteen@comcast.net.

 

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[i] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses.Anesthesiology. Feb 1982;56(2):119-136.

 

[ii] Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain. 1999;82(2):111-125.

Pittenger C, Sanacora G, Krystal JH. The NMDA Receptor as a Therapeutic Target in Major Depressive Disorder. CNS and Neurological Disorders – Drug Targets. 2007;6:101-115.

 

[iii] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

 

[iv] Fine J, Finestone SC. Sensory disturbances following ketamine anesthesia: recurrent hallucinations. Anesth Analg. May-Jun 1973;52(3):428-430.

Meyers EF, Charles P. Prolonged adverse reactions to ketamine in children. Anesthesiology.Jul 1978;49(1):39-40.

Perel A, Davidson JT. Recurrent hallucinations following ketamine. Anaesthesia. Oct 1976;31(8):1081-1083.

 

[v] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

 

[vi] Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. Nov 1978;133:429-435.

 

[vii] Innovative Drug Delivery Systems I. Investigator’s Brochure, v7, PMI-100/150 (intranasal ketamine 100 – 150 mg/mL)1995.

 

[viii] Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. Aug 1996;77(2):203-207.

 

[ix] Green SM, Rothrock SG, Lynch EL, et al. Intramuscular Ketamine for Pediatric Sedation in the Emergency Department: Safety Profile in 1,022 Cases. Annals of Emergency Medicine.1998;31(6):688-697.

 

[x] Green SM, Roback MG, Kennedy RM, Krauss B. Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update. Ann Emerg Med. Jan 20 2011.

 

[xi] Khorramzadeh E, Lotfy AO. Personality predisposition and emergence phenomena with ketamine. Psychosomatics. 1976;17(2):94-95.

 

[xii] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

 

[xiii] Abrams R, Morrison JE, Villasenor A, Hencmann D, Da Fonseca M, Mueller W. Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures. Ansethsia Progress. 1993;40(3):4.

Diaz J. Intranasal ketamine preinduction of paediatric outpatients. Pediatric Anesthesia.1997;7(4):273-278.

Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans: Psychotomimetic, Perceptual, Cognitive, and Neuroendocrine Responses. Arch Gen Psychiatry.March 1, 1994 1994;51(3):199-214.

White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses.Anesthesiology. Feb 1982;56(2):119-136.

Howes MC. Ketamine for paediatric sedation/analgesia in the emergency department.Emerg Med J. May 2004;21(3):275-280.

Weksler N, Ovadia L, Muati G, Stav A. Nasal ketamine for paediatric premedication. Can J Anaesth. Feb 1993;40(2):119-121.

Green SM, Roback MG, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. Aug 2009;54(2):158-168 e151-154.

Green SM, Rothrock SG, Lynch EL, et al. Intramuscular Ketamine for Pediatric Sedation in the Emergency Department: Safety Profile in 1,022 Cases. Annals of Emergency Medicine.1998;31(6):688-697.

Khorramzadeh E, Lotfy AO. Personality predisposition and emergence phenomena with ketamine. Psychosomatics. 1976;17(2):94-95.

 

[xiv] White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses.Anesthesiology. Feb 1982;56(2):119-136.

Slogoff S, Allen GW, VWessels JV, Cheney DH. Clinical Experience with Subanesthetic Ketamine.Anesthesia and Analgesia. May-June 1974;53(3):354-358.

Byer DE, Gould ABJ. Development of Tolerance to Ketamine in an Infant Undergoing Repeated Anesthesia. Anesthesiology. 1981;54(3):255-256.

Cronin MM, Bousfield JD, Hewett EB, McLellan I, Boulton TB. Ketamine anaesthesia for radiotherapy in small children. Anaesthesia.1972;27(2):135-142.

 

[xv] Dotson JW, Ackerman DL. Ketamine Abuse.Journal of Drug Issues. 1995;25(4):751-757.

 

[xvi] Pittenger C, Sanacora G, Krystal JH. The NMDA Receptor as a Therapeutic Target in Major Depressive Disorder. CNS and Neurological Disorders – Drug Targets. 2007;6:101-115.

Zarate CA, Jr., Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. Aug 2006;63(8):856-864.

Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. Aug 2010;67(8):793-802.

Liebrenz M, Borgeat A, Leisinger R, Stohler R. Intravenous ketamine therapy in a patient with a treatment-resistant major depression. Swiss Med Wkly. Apr 21 2007;137(15-16):234-236.

 

[xvii] Pittenger C, Sanacora G, Krystal JH. The NMDA Receptor as a Therapeutic Target in Major Depressive Disorder. CNS and Neurological Disorders – Drug Targets. 2007;6:101-115.

[xviii] Li N, Lee B, Liu R, et al.(2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science; 329:959-964.

Prevalence of Chronic Pain After Traumatic Brain Injury: A Systematic Review

Prevalence of Chronic Pain After Traumatic Brain Injury: A Systematic Review

Devi E. Nampiaparampil, MD. 

http://jama.jamanetwork.com/Mobile/article.aspx?articleid=182384

Author Affiliations: Departments of Internal Medicine and Neurology and Rehabilitation, Veterans Affairs Central California Healthcare System, Fresno.

JAMA. 2008;300(6):711-719. doi:10.1001/jama.300.6.711.

ABSTRACT

Context The Centers for Disease Control and Prevention estimates that approximately 1.4 million US individuals sustain traumatic brain injuries (TBIs) per year. Previous reports suggest an association between TBI and chronic pain syndromes (eg, headache) thought to be more common in patients with mild TBI and in those who have sustained brain injury from violent rather than unintentional trauma. Comorbid psychiatric disorders such as posttraumatic stress disorder (PTSD) may also mediate chronic pain symptoms.

Objectives To determine the prevalence of chronic pain as an underdiagnosed consequence of TBI and to review the interaction between chronic pain and severity of TBI as well as the characteristics of pain after TBI among civilians and combatants.

Evidence Acquisition The Ovid/MEDLINE database was searched for articles published between 1951 and February 2008 using any combination of the terms brain injury, pain,headache, blast injury, and combat (combat disorders, war, military medicine, wounds and injuries, military personnel, veterans). The PubMed and MD Consult databases were searched in a similar fashion. The Cochrane Collaboration, National Institutes of Health Clinical Trials Database, Meta-Register of Current Controlled Trials, and CRISP databases were searched using the keyword brain injury. All articles in peer-reviewed journals reporting original data on pain syndromes in adult patients with TBI with regard to pain prevalence, pain category, risk factors, pathogenesis, and clinical course were selected, and manual searches were performed of their reference lists. The data were pooled and prevalence rates calculated.

Evidence Synthesis Twenty-three studies (15 cross-sectional, 5 prospective, and 3 retrospective) including 4206 patients were identified. Twelve studies assessed headache pain in 1670 patients. Of these, 966 complained of chronic headache, yielding a prevalence of 57.8% (95% confidence interval [CI], 55.5%-60.2%). Among civilians, the prevalence of chronic pain was greater in patients with mild TBI (75.3% [95% CI, 72.7%-77.9%]) compared with moderate or severe TBI (32.1% [95% CI, 29.3%-34.9%]). Twenty studies including 3289 civilian patients with TBI yielded a chronic pain prevalence of 51.5% (95% CI, 49.8%-53.2%). Three studies assessed TBI among 917 veterans and yielded a pain prevalence of 43.1% (95% CI, 39.9%-46.3%). PTSD may mediate chronic pain, but brain injury appears to have an independent correlation with chronic pain.

Conclusions Chronic pain is a common complication of TBI. It is independent of psychologic disorders such as PTSD and depression and is common even among patients with apparently minor injuries to the brain.

The Centers for Disease Control and Prevention estimates that approximately 1.4 million US individuals sustain traumatic brain injuries (TBIs) per year.1The diagnosis can be made subjectively by assessing patients for loss of consciousness (LOC), altered consciousness after a head injury, or posttraumatic amnesia.2 These head injuries can be sustained either when the head forcefully hits an object, when an object penetrates the skull, or when brain tissue undergoes a sudden acceleration, deceleration, or both.

Since 2001, the United States has deployed more than 1.5 million military personnel to Iraq and Afghanistan.3 A higher percentage of these soldiers are now able to survive injuries that would have been fatal in previous wars.4 Among combatants who have returned to the United States, the prevalence of head injuries is estimated at 15.1%.3Multiple studies have highlighted the importance of brain injuries to US military personnel in Iraq and Afghanistan. Studies of selected military units in Iraq reported that 88% to 97% of their soldiers have sustained blast injuries while in combat5,6 and that 47% to 59% of these soldiers have sustained injuries to the head and neck suggestive of TBI.5- 8The Defense and Veterans Brain Injury Center estimates that 10% to 20% of all soldiers returning from duty in Iraq and Afghanistan have sustained some type of TBI.9 As of 2008, at least 25 000 soldiers have been diagnosed with TBI, with a projected cost of $14 billion for their care over the next 20 years.9

The association of TBI and chronic pain was described as early as 1915 in troops returning from World War I with “shell shock.”10 Other studies have supported the association between TBI and chronic pain syndromes, the most common of which is headache. One study of Operation Iraqi Freedom/Operation Enduring Freedom veterans experiencing postconcussive syndrome found that posttraumatic stress disorder (PTSD) accounted for all symptoms except pain, suggesting that pain is physiologically linked to brain injury.3

Given the morbidity associated with chronic pain, the strategies available for its early treatment, and the financial burden it imposes on patients and society, this review was undertaken to (1) determine the prevalence of chronic pain syndromes such as headache among patients with TBI; (2) discuss other potential pain syndromes in these patients; (3) describe the relationship between pain and severity of brain injury; (4) investigate the effect of civilian vs combat veteran status on chronic pain after TBI; and (5) examine the role of psychiatric comorbid disorders such as depression, PTSD, and/or substance disorders in posttraumatic pain.

EVIDENCE ACQUISITION

Studies were identified that could provide information on the prevalence of pain among adult patients with TBI. The Ovid/MEDLINE database was searched for articles published between 1951 and February 2008 using any combination of the terms brain injury, pain, headache, blast injury, andcombat (combat disorders, war, military medicine,wounds and injuries, military personnel, andveterans). The PubMed and MD Consult databases were searched in a similar fashion for additional articles. The Cochrane Collaboration, National Institutes of Health Clinical Trials Database, Meta-Register of Current Controlled Trials, and CRISP databases were searched using the keyword brain injury.

All selected articles were published in peer-reviewed journals and contained original data on pain syndromes after TBI with respect to prevalence, pain category, risk factors, pathogenesis, and clinical course. Manual searches were performed of the reference lists of selected articles, and the authors of 2 selected studies were contacted for additional citations. The search was not limited by language or publication status. No randomized controlled studies were found in the search (all patients were recruited into studies after the brain injury had occurred). Case reports and review articles were cited only if no other data were available (Figure).

Figure. Selection of Articles for Inclusion in Review

 

TBI indicates traumatic brain injury.

The initial search yielded 1067 articles, and 43 others were selected from the reference lists of retrieved articles. Of these 1110 articles, 1087 were excluded because they did not fulfill the primary inclusion criteria; ie, the prevalence of chronic pain in their TBI populations could not be calculated. Three studies that met all other criteria were excluded because they focused on individuals younger than 16 years. Two abstracts of unpublished data were also included. The 3 experts contacted for this study were not aware of any negative studies that had not been published.

The data from the final 23 studies were pooled by adding results across studies. Since the studies were cross-sectional (15), prospective observational (5), or retrospective (3), none were given additional weighting. The data from the studies evaluating headache were pooled to determine the overall prevalence of headache among patients with TBI. Subsequently, the studies having groups of patients with mild TBI were compared with the studies having groups of patients with severe TBI to assess respective prevalences of chronic pain. Mild TBI was defined according to American College of Rehabilitation Medicine criteria (Box 1).2 Studies in which the investigators defined the patients as having mild TBI or severe TBI were also included. The studies were then compared with respect to chronic pain between groups of civilians and military survivors.

Box 1. Acute Symptoms of Mild Brain Injury: Definition of Mild Traumatic Brain Injury According to the American Congress of Rehabilitation Medicine2

1. Any period of loss of consciousness;

2. Any loss of memory for events immediately before or after the accident;

3. Any alteration in mental state at the time of the accident (eg, feeling dazed, disoriented, or confused); and

4. Focal neurological deficit(s) that may or may not be transient; but where the severity of the injury does not exceed the following:

• Posttraumatic amnesia not greater than 24 h

  After 30 min, an initial Glasgow Coma Scale score of 13-15

  Loss of consciousness of approximately 30 min or less

P values were derived by significance testing of 2 population-proportions using a 2-proportion z test with unequal variances. The results of each individual study were compared with those of the studies combined. The prevalence rates of pain were calculated with 95% confidence intervals (CIs) in each single study and in the pooled data. Analyses were performed using SAS version 9.1 (SAS Institute Inc, Cary, NC); P < .05 was considered statistically significant.

EVIDENCE SYNTHESIS

Jump to Section [+]

Traumatic brain injury can have detrimental consequences (Box 2).11- 13Table 114- 34 and Table 23,35,36 provide a summary of the articles selected for review. Twenty-three studies including 4206 patients reported on the prevalence of chronic pain after TBI.

Box 2. Clinical Characteristics of Traumatic Brain Injury (TBI)

Mild TBI Can Lead to Deficits in

• Cognition

  Attention

  Memory

  Calculation

  Judgment

  Insight

  Reasoning

• Sensory processing

  Sight

  Hearing

  Touch

• Communication

  Language expression

  Understanding

• Social function

  Compassion

  Interpersonal social awareness

• Mental health

  Depression

  Anxiety

  Personality changes

  Aggression/irritability

  Social inappropriateness

• Sleep disturbance

  Vertigo/dizziness

Moderate to Severe TBI Can Have Additional Consequences

• Abnormal states of consciousness

• Deficits in speech and swallowing

• Cranial neuropathies

• Paresis/paralysis

• Complications of prolonged bed rest

• Seizure disorders

• Movement disorders

All patients can exhibit signs and symptoms of trauma in addition to these symptoms.11- 13

Table 1. Pain Prevalence in Adult Patients With Traumatic Brain Injury (TBI)a

Table 2. Pain Prevalence In Military Survivors With Traumatic Brain Injury (TBI)a

Headache

Twelve studies14,19,23- 25,27,29- 34 reported on headache prevalence after TBI. Of the 1670 patients included in these studies, 966 reported experiencing chronic headache, yielding a prevalence of 57.8% (95% CI, 55.5%-60.2%). Selected studies suggest that headache is a common physical manifestation of TBI14,19,23- 25,27,29- 34 and that patients with preexisting headache syndromes often experience worsening of their prior symptoms.23,25

De Benedettis and De Santis19 retrospectively studied 130 consecutive patients with TBI admitted to a university hospital in Milan, Italy. Patients with preexisting headache or who had required neurosurgery were excluded. Pain prevalence was not stratified by injury severity, but descriptive information about TBI severity was provided. After the initial injury, 26% had no change in mental status, 35% had “brief” LOC, 25% were in a superficial coma, 9% were in a coma of intermediate severity, and 5% were in a deep coma. Computed tomography (CT) scans were performed in 65%, with normal results. Sixteen percent of the patients were reevaluated between 6 and 12 months after the injury, 47% were reassessed at 2 years, and 37% had a longer follow-up period that was variable in duration. Posttraumatic headache was reported by 44% of patients after 6 months.Posttraumatic headache began at the time of injury in 30% of patients, between 15 days and 1 month in 21%, between 1 and 3 months in 18%, and after 3 months in 32%. Eleven percent still had headache at 6 months, 54% at 1 year, and 30% after 2 years. The majority of patients (52%) complained of headache of moderate intensity (3-7 on a visual analog scale). Fifty-six percent experienced headache between 4 and 15 times per month. The majority of headaches (51%) occurred in the occipital region. However, among these patients with TBI, no significant relationship was found between the location of the head trauma and the location of pain.

Jensen and Nielsen,23 assessing patients 9 to 12 months after injury, interviewed 168 of 233 patients with suspected cerebral concussion who were admitted over a 1-year period to a county hospital in Denmark. Although 49% of these patients had been hospitalized for a mean duration of 4.3 days, all participants were classified as having sustained mild TBI. Jensen and Nielsen excluded patients with LOC longer than 24 hours, cerebral contusion, or intracerebral hemorrhage. Of the included patients, 29% reported no LOC, 44% had LOC less than 15 minutes, and 39.9% had preexisting headache. After the trauma, 64.3% of patients had headaches, with 34.3% experiencing worsening of their preexisting headache. Four patients (2.4%) reported that their baseline headaches had decreased after the trauma. This is the only selected study that comments on resolution of headache after trauma.

Rimel et al30 studied 538 patients with mild TBI (defined in that study as LOC shorter than 20 minutes, Glasgow Coma Scale [GCS] score of 13 to 15, and hospital length of stay shorter than 48 hours) and conducted interviews with 79%. The 538 patients constituted all of the mild TBIs seen at a university hospital over a 20-month period. Of these patients, 66% were male. Almost half of the patients had been injured in motor vehicle crashes, and 43% had positive blood alcohol levels. Four hundred twenty-four were followed up at 3 months postinjury; of these, 79% had persistent headaches. Of the patients employed at the time of the injury, only 66% remained employed at 3 months.

Uomoto and Esselman33 evaluated 104 patients seen in an outpatient TBI rehabilitation program. Of these, 63.5% were male, 36.5% were female, and the average time postinjury was 26 months. Patients with mild TBI had LOC shorter than 1 hour and GCS scores of 13 to 15, while those with moderate to severe TBI had LOC longer than 1 hour and GCS scores of 12 or less. Of patients with mild TBI, 89% reported headache, compared with 18% of those with severe TBI (P < .001), but similar rates were found for chronic neck/shoulder, back, and other pain symptoms. The group with mild TBI also had a higher frequency of concomitant pain syndromes.

Other Potential Pain Syndromes

Some of the most mystifying pain conditions were first observed during times of war.37 For example, complex regional pain syndrome (CRPS), formerly known as reflex sympathetic dystrophy, was first described after the American Civil War. In 1992, Gellman et al21 addressed the issue of CRPS in patients with TBI. In that study, 100 patients admitted consecutively to an inpatient rehabilitation unit with GCS scores less than 8 were evaluated for signs of CRPS. On average, the patients were 4 months post-TBI. During their hospitalizations, 13 patients developed clinical signs and symptoms of CRPS such as pain withdrawal response, vasomotor and temperature changes, discoloration, and palmar fibrosis; these patients underwent formal testing. Of these 13 patients, 12 had bone scan results consistent with CRPS in the upper extremity. These patients also had a combined total of 8 peripheral nerve injuries, 4 fractures, 2 joints with periarticular heterotopic ossification, 1 shoulder dislocation, and 1 rotator cuff tear. Gellman et al found a 12% incidence of CRPS post-TBI, as compared with the 12.5% to 25% incidence of CRPS reported after stroke. 37

Garland et al20 retrospectively reviewed the records of 496 adults with severe TBI admitted to a head trauma service over a 4-year period and, after excluding patients with traumatized joints, found that 100 joints in 57 patients (11%) had painful heterotopic ossification with decreased range of motion in the adjacent joint. Workup for heterotopic ossification was initiated when examiners elicited painful resistance to movement at a joint.

In terms of peripheral neuropathic pain, in a study of 132 inpatients with TBI,18 15 were found to have flaccidity for longer than 1 month, areflexia for longer than 1 month, and abnormal motor patterns. These patients underwent nerve conduction studies and electromyography, and 13 of 132 (10%) were diagnosed with peripheral neuropathies. The mean time elapsed between the trauma and diagnosis was 51 days (range, 14-170). Of the 13 patients, 3 had preventable pressure palsies and 4 had developed signs and symptoms of CRPS.18 This study might not have captured several pain syndromes that can afflict patients. For example, central/deafferentation pain (eg, phantom limb pain) has been cited after TBI.38

Neuromuscular spasticity is often seen in patients with severe TBI. It is theorized to directly cause pain as well as to indirectly lead to painful conditions such as subluxation, tendinitis, and capsulitis.39However, the presence of pain due to spasticity, as well as the ability of pain to exacerbate preexisting spasticity, has not been well studied,39 and this literature search did not reveal any studies delineating the prevalence of pain in the population of patients with TBI who experience spasticity.

Severity of Brain Injury

Ten studies14- 16,23,24,27,30,32- 34 reported the prevalence of pain in patients with mild TBI. Of the 1046 patients included in these studies, 788 reported pain, producing a prevalence rate of 75.3% (95% CI, 72.7%-77.9%). Nine studies16- 18,20- 22,24,33,34 furnished data on the prevalence of pain in patients with severe TBI. Of the 1063 patients included in these studies, 341 reported chronic pain, producing a prevalence rate of 32.1% (95% CI, 29.3%-34.9%).

Although this review confirmed the clinical perception that patients with mild TBI have a higher prevalence of chronic pain syndromes than those with moderate to severe TBI (P < .001), it remains unclear why this should be so. Part of the problem may be that patients with more severe TBI may have difficulty reporting or processing their symptoms because of memory disturbances, language deficits, and executive dysfunction.40

Combat Veterans

Given that TBI is the hallmark injury of the current conflicts in Iraq and Afghanistan,9 the high prevalence of chronic pain after TBI is of particular significance. Our literature search produced 3 studies3,35,36 including a total of 917 combat veterans with data regarding the prevalence of pain among patients with combat-associated brain injuries. Of these 917 patients, 395 complained of pain, yielding an estimated prevalence rate of 43.1% (95% CI, 39.9%-46.3%). These 3 studies3,35,36 described 329 of the 917 combat veterans as having headache, producing a prevalence rate of 35.9% (95% CI, 32.8%-39.0%). Twenty studies14- 34 including a total of 3289 civilian patients with TBI yielded a chronic pain prevalence of 51.5%.

Hoge et al3 performed a large cross-sectional study of 2525 US Army Infantry soldiers with combat exposure in Iraq or Afghanistan. Of these, 95.5% were men and 55.5% were younger than 30 years. Of those soldiers who had attended study recruitment meetings, 59% completed the study. The lack of availability for soldiers to complete the questionnaires was attributed to normal transfers and training, although it is possible that soldiers with more serious illnesses and injuries did not have the opportunity to participate. Although the study used a convenience sample, it appears to be representative of Operation Iraqi Freedom/Operation Enduring Freedom veterans. The soldiers were questioned at 3 to 4 months after their return to the United States to provide an appropriate amount of time to assess for postconcussive symptoms while minimizing recall bias. Of the soldiers completing the study, 4.9% experienced LOC shorter than 30 minutes, and 10.3% had alterations in mental status without LOC. Criteria for PTSD were met by 43.9% of soldiers with LOC and 27.3% of those with altered mental status without LOC; PTSD also was diagnosed in 16.2% of the soldiers with injuries other than TBI and in 9.1% of uninjured soldiers. Controlling for other factors, LOC and combat intensity remained significantly associated with PTSD (odds ratio for LOC, 2.98 [95% CI, 1.70-5.24]; for highest vs lowest quartiles of combat intensity, 11.58 [95% CI, 2.99-44.82]), and LOC was independently associated with the diagnosis of major depression (odds ratio, 3.67 [95% CI, 1.65-8.16]). After adjusting for PTSD and depression, TBI was no longer correlated with any physical health symptoms except for headache pain.

Walker et al35 evaluated 109 patients with severe TBI seen consecutively at 1 of 4 rehabilitation Veterans Affairs medical centers. These patients were seen for acute rehabilitation and reevaluated at 6 and 12 months. Of the 109 patients, 38% had acute postconcussive headache, with 48.8% experiencing this in the frontal area; 75.6% had daily headache. No relationship was found between the presence of headache and demographic, injury severity, or emotional variables. Improvement at 6 months was associated with less anxiety and depression. Of the patients who had headache at 6 months, 95.5% continued to have headache at 12 months. At the times of follow-up, the severity of posttraumatic headache had decreased.

Contrary to expectations, the prevalence rate of pain after TBI appears to be higher in civilians than in combat veterans. This could be due to a variety of reasons. Military survivors may be less likely to report pain because of factors such as peer pressure or fear of being medically evaluated and perhaps separated from fellow soldiers. Conversely, civilians may be more likely to overreport their pain, potentially for secondary gain. Or, since convenience samples were used, civilians with unresolved pain may be recruited more frequently into these studies. The characteristics of the samples may differ as well.

Military personnel may be healthier than their civilian cohorts. Previous studies have suggested that pain in soldiers is primarily due to the increased level of physical activity experienced during military training.41

Of the 3 studies of combat veterans,3,35,36 2 were performed immediately after the soldiers returned from deployment.35,36 It could be argued that this was too early for chronic posttraumatic headache to develop. However, in a retrospective study of 70 civilian outpatients experiencing posttraumatic headache, 35% developed the headache within an hour of the initial trauma, 14% within 24 hours, and 27% within 7 days. Of the 70 outpatients, 56% described chronic daily headache with symptoms for at least 21 of the 30 days recorded. Most patients reported that the pain was of at least moderate intensity and often interfered with work-related and other functional activities.42

Finally, given the importance that the Departments of Defense and Veterans' Affairs have placed on TBI screening among returning soldiers as well as the overlap in criteria between TBI and PTSD among other psychiatric disorders, the number of true TBIs in the military sample may be overestimated. This in turn may dilute the sample and cause an underestimation of the true prevalence of pain in that population.

Military survivors with brain injuries  have a variety of pain syndromes. In the survey by Hoge et al,3 in those soldiers who reported having sustained TBI during deployment (as compared with soldiers having other injuries), 32.2% had headache (P < .001), 14.0% had chest pain (P < .001), and 8.3% had pain or problems during sexual intercourse (P = .04). Although the difference between groups was not statistically significant, individuals with TBI also reported stomach pain (11.7%), back pain (33.1%), and arm, leg, or joint pain (37.2%).

It is possible that individuals having TBI due to violent trauma, such as assaults, have increased pain compared with those having TBI due to unintentional trauma, such as sports injuries or falls.43 This review could not distinguish civilians who had sustained TBI through random violence from the rest of the sample. Although patients who had sustained violent injuries were not excluded from any of the studies reviewed, none of the studies created subgroups based on mechanism of injury.

Psychiatric Disorders

The relationship between pain and mood disorders such as depression is complex. Hoffman et al22evaluated 146 of 202 consecutive patients during inpatient rehabilitation and at 1 year postinjury. These patients had severe TBI, defined as a GCS score of 12 or less. Of the 146 patients, 76% were male and 24% were female; 78.1% were white and 21.9% were of other race/ethnicity; and 48.6% were injured in motor vehicle crashes and 11.6% through violence. Of the evaluated patients, 72.6% had pain 1 year out from their injuries, and 55% reported interference with activities of daily living. The mean bodily pain score on the 36-Item Short-Form Health Survey was 66.7 on a scale of 100. Higher pain scores at 1 year postinjury were associated with depression during inpatient rehabilitation, female sex, and race/ethnicity other than white. Pain was associated with community participation, but, when depression was factored in, the pain variable lost significance. This study underscores the relationship between pain and mood disorders.

Bryant et al17 examined 96 of 161 patients admitted for severe TBI to a tertiary-care TBI unit to determine whether there was a relationship between pain and PTSD measures. In that study, 22 patients were excluded because of cognitive dysfunction causing them to be unable to understand or respond to the interviewer. The final population was evaluated between 5 and 7 months posttrauma. Chronic pain was defined as pain at least once a week of greater than 6 months' duration. The McGill Pain Questionnaire and a 10-point scale were used to assess pain complaints. Of the included patients, 62% reported chronic pain, 24% reported daily pain, and 7% reported constant pain. Bryant et al found that higher pain severity was associated with increased severity of PTSD, depression, poor satisfaction with life, and avoidant coping style. After controlling for the effects of PTSD, the only factor that still correlated with pain severity was avoidant coping style.

Other studies have supported the relationship between chronic pain syndromes and PTSD.44- 47Trauma patients with multiple symptoms of PTSD generally report higher levels of pain and affective disturbances than those who do not have many symptoms of PTSD.48

The relationship between brain injury and PTSD has been debated since 1939, when Schaller31surmised that the rate of pain in posttrauma psychoneurotic states would be greater than that in patients with TBI. In the cohort of 100 patients with TBI in that study, 77% had persistent headache, which was similar to the rate of headache (97%) in patients with “posttraumatic psychoneurosis or hysteria.”

PTSD may be associated with increased pain severity for many reasons. Pain perception can be heightened by increased anxiety, and the ability to cope with pain in PTSD may be impeded by catastrophic interpretations of pain. In addition, patients may not have the concentration required, due to intrusive thoughts, to use cognitive strategies to reduce pain. Alternatively, they may display an attentional bias to negative events. Finally, the concordance between PTSD and somatoform pain disorder is high.17

Although several studies attest that substance abuse may be a causative factor in the occurrence,49 severity,50 and prognosis50 of TBI, no studies have examined the relationship between substance abuse and pain after TBI. It is possible, however, that patients may use illicit substances to self-medicate for pain.

COMMENT

This review is limited by several factors. First, all of the studies were cross-sectional, observational, or retrospective. Second, the civilian study populations demonstrated heterogeneity in terms of comorbid psychiatric disorders, cause of injury, and time elapsed since injury, as well as in the recruitment procedures. Patients were recruited from rehabilitation units and clinics but not from skilled nursing facilities, where the most severely injured patients might reside. All of the studies used convenience samples rather than random samples.Third, all of the information gathered relied on patient report. It is possible that patients with TBI who had more cognitive dysfunction were unable to comprehend or accurately respond to questions about their pain. Fourth, the definition of TBI varied across studies, as did the definitions and measures of chronic pain. Fifth, most studies did not provide information key to subgroup analyses.

Further research in brain injury would benefit from standardized criteria for measurement of severity of TBI. Data analysis would be enhanced by reporting of symptoms based on severity, mechanism, and duration of injury, as well as on comorbid psychiatric disorders.

Chronic pain is a common complication of TBI and contributes to morbidity and potentially poor recovery after brain injury. Patients who appear clinically to have less severe brain injuries may in fact develop more pain symptoms. Patients who have sustained TBIs in combat have a higher rate of chronic pain than the general population. However, they appear to have lower rates of pain than civilians with TBI. Patients with TBI would benefit from early screening and treatment for pain syndromes to decrease the morbidity that untreated chronic pain additionally imposes on them and on society. In addition, clinicians treating patients who have any history of mild head injuries should consider inquiring further about coexisting symptoms. These may affect how the patients comprehend and follow treatment recommendations.

AUTHOR INFORMATION

Corresponding Author: Devi E. Nampiaparampil, MD, Department of Neurology and Rehabilitation, Veterans Affairs Central California Healthcare System, 2615 E Clinton Ave, Fresno, CA 93703 (devichechi@gmail.com).

Author Contributions: Dr Nampiaparampil had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosures: Dr Nampiaparampil reported previously serving on a research advisory board for Elan Pharmaceuticals.

Additional Contributions: I thank Daphne Perry (VA Central California Healthcare System) for expeditiously acquiring the articles reviewed in this meta-analysis, Robert Nampiaparampil, MD (Northwestern University Feinberg School of Medicine), for his indispensable statistical and technical contributions, and John Pang, MD (Division of Cardiology, Northwestern Memorial Hospital), for his insightful comments and invaluable editorial recommendations. None of these individuals received compensation for their contributions.

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