Pathways to Understanding the Biological Mechanisms of Pain: ‘Moving Pain’ Targets and ‘Multiple Analgesic’ Targets

Pathways to Understanding Biobehavioral Responses to Pain in Pediatric Patients

Pathways to Understanding Self-Management Interventions for Chronic Pain

Some pain medications work better for certain people than others. Some work better for different types of pain or at different times in a painful experience. Why is this so? Part of the answer, scientific evidence now suggests, might be written into our genes.

To better understand these important aspects of pain, scientists at the National Institute of Nursing Research (NINR) are using genetic and proteomic tools to explore the cellular mechanisms that underlie pain symptoms. The NINR Intramural Research Program (IRP), under the direction of Dr. Raymond Dionne, is composed of a multi-disciplinary team of scientists that are analyzing genetic variations among individuals to understand responses to analgesic (pain-reducing) medications. The team hopes to develop diagnostic tools that use ‘biomarkers,’ biological substances that can be detected in the blood or by other methods that will allow researchers and clinicians to rapidly assess an individual’s pain response.

Interrupting the Cascade of Pain

Dr. Dionne began his work in the 1970’s in clinical trials of ibuprofen (e.g., Advil™, Motrin™, Nuprin™), a  common, non-prescription analgesic that is often used to relieve pain after dental surgery. He found a correlation between the course of an individual’s postoperative pain response and the “inflammatory cascade” of chemical mediators triggered by tissue injury from the surgery. Inflammation is a common response of the body to various types of injury or infection. It is caused when the release of certain compounds into the area around the injury leads to the release of other compounds in a cascade effect that may work to constrict blood vessels, isolate the area of injury, and activate the immune system. Inflammation also contributes to the sensation of pain. Interrupting this inflammatory cascade, Dr. Dionne theorized, might help to decrease the pain patients feel. However, little was understood of how ibuprofen and other similar medications, known collectively as nonsteroidal anti-inflammatory drugs (NSAIDs), affected the inflammatory response.

Moving Pain Targets and Multiple Analgesic Targets

Dr. Dionne’s innovative approach to understanding the biological and biobehavioral mechanisms associated with pain continues within a number of collaborations between the NINR IRP, other NIH investigators, and academic programs. The multi-disciplinary, independent principal investigators of the IRP are unraveling the role of novel multiple analgesic targets for pain treatment. Using a concept called ‘moving pain targets,’ their work focuses on pain response cascades such as tissue injury, inflammation, and signal transduction that reflect multiple molecular and cellular pathways operating in parallel in response to pain at both the peripheral and central nervous system level. Each pathway may produce a different form of pain that could provide the opportunity for targeting by multiple analgesic strategies. The molecular events that occur at each level, in turn, produce unique human responses driven by injury-induced gene expressions to alter how the body responds across individuals, tissue injuries, or even over time. Identifying how these events occur and why may drive a new line of study in pharmacogenetics.(1)

Genetic Variations in Pain Response

Investigators of the IRP are exploring the molecular pathways that are involved in inflammation. Among the most important are a class of compounds called prostaglandins.

Prostaglandins are hormone-like substances that contribute to pain and inflammation. Two enzymes in the cells of the body are commonly involved in producing prostaglandins, cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2).  COX-1 is active in cells throughout the body, while COX-2 is most active at the site of an injury. The principle action of NSAIDs (non-steroidal anti-inflammatory drugs) in relieving pain is to block prostaglandin synthesis by inhibiting one or both of these enzymes.

In one study involving patients receiving dental surgery, the IRP scientists looked at the changes in the activity of the genes that encode for COX-1 and COX-2 over time and variations across individuals. They found that the gene encoding for COX-1 decreased in expression shortly after the surgery, while expression of the gene for COX-2 increased almost three-fold, before returning to near-baseline levels within 48 hours. However, the research team noted a wide variation in the expression of the gene for COX-2 based on different forms, or ‘alleles’, of the gene. For pain relief, patients in the study received either ibuprofen, which inhibits both COX-1 and COX-2, or rofecoxib (Vioxx™, since removed from the market), which selectively inhibits COX-2.

Wide variations in pain sensation were reported. Those with alleles that led to increased activity for COX-2 gene shortly after surgery responded better to rofecoxib, while those with alleles that resulted in a smaller increase in activity of the COX-2 gene benefitted more from ibuprofen. These findings stress the importance of being able to assess individual responses to pain medications to improve individual pain management and contribute to drug safety.(2)

Dr. Dionne’s colleagues also found that the analgesic acetaminophen (e.g. Tylenol™), a common drug used to relieve fever, pain and inflammation, selectively suppresses prostaglandin E2 (PGE2) release without inhibiting the release of thromboxane. PGE2 is a hormone-like substance released by blood vessel walls in a cascaded response to inflammation. This response acts on the brain to induce fever. Thromboxane is a substance made by platelets in the blood that promotes clotting and constriction of the blood vessels, which is an important response to injury.

While acetaminophen is well-known for its ability to safely relieve pain and decrease fever, its mechanism of action is not well understood. Its effects during the first three hours after surgery were compared with rofecoxib (Vioxx®) and another medication, ketorolac, which suppresses both COX-1 and COX-2 (a major contributor to pain associated with inflammation). All three medications decreased post-surgical pain, although ketorolac was the most effective. As expected, ketorolac suppressed the production of both prostaglandins and thromboxane, which is produced primarily by COX-1. Both rofecoxib and acetaminophen suppressed prostaglandins but had little effect on thromboxane. This finding indicates that acetaminophen appears to act as a selective COX-2 inhibitor in the body.(3)

Taking a closer look at the role that different proinflammatory mediators play in initiating and maintaining inflammation induced by tissue injury, using a variety of genetic research techniques, the team showed that rofecoxib (a selective COX-2 inhibitor) and ketorolac (a nonselective COX inhibitor) had no significant effect on TNF-α gene expression in oral mucosal tissue biopsies three hours after dental surgery. Instead, these two mechanisms down-regulated the gene and protein expression of yet another compound, phosphodieterase type 4 (PDE4D), which might represent a novel mechanism contributing to analgesic and anti-inflammatory effects.(4)

The NINR IRP continues to support collaborative, interdisciplinary approaches to pain research within a broad program of basic and clinical research. In future studies, the team will use technologies such as gene chips in studies of pain that will allow scientists to further characterize molecular-genetic mechanisms of pain and analgesia, identify new targets for analgesic drugs, and test the efficacy and adverse reactions of newly developed or currently used drugs to treat pain. Their discoveries in understanding the molecular and genetic factors that contribute to pain symptoms, the subsequent behavioral changes associated with painful stimuli, the evaluation of the effects of pain symptoms on quality of life, and the creation of prototypic interventions to improve pain therapy will increase our understanding of the interrelationship among an individual’s personal genetic makeup and their response to pain. Thanks to the work of the NINR IRP, these discoveries move us closer to developing new medications to treat pain more safely and effectively.

For more information on the NINR Intramural Research program, please visit our web site at: http://www.ninr.nih.gov/ResearchAndFunding/DivisionofIntramuralResearch/default.html  

1 Woodcock J, Witter J, Dionne RA. Stimulating the development of mechanism-based, individualized pain therapies. Nature Reviews Drug Discovery, 2007 Sept; 6(9) 703-710.

PubMed: http://www.ncbi.nlm.nih.gov/sites/entrez/17762885

2 Lee YS, Kim H, Wu TX, Wang XM Dionne RA. Genetically mediated interindividual variation in analgesic responses to cyclooxygenase inhibitory drugs. Clin Pharmacol Ther 2006 79:407-418.

PubMed: http://www.ncbi.nlm.nih.gov/sites/entrez/16678543  

3 Lee YS, Kim H, Brahim JS, Rowan J, Lee G, Dionne RA. 3 Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation. Pain 2007 Jun; 129(3):279-286.

PubMed: http://www.ncbi.nlm.nih.gov/sites/entrez/17175104

4 Wang XM, Hamza M, Gordon SM, Wahl SM, Dionne RA. COX inhibitors downregulate PDE4D expression in a clinical model of inflammatory pain. Clinical Pharmacol Ther, 2008 Jul: 84(1):39-42.

PubMed: http://www.ncbi.nlm.nih.gov/sites/entrez/18288087

Pathways to Understanding Biobehavioral Responses to Pain in Pediatric Patients

The assessment of biobehavioral responses to pain is essential for proper patient management, but pain assessments that lead to appropriate treatment interventions can be particularly challenging in infants and children. National Institute of Nursing Research (NINR)-supported scientists are tackling these challenges through a number of studies that examine the effects of pain and pain management from preterm infants to young children with special medical needs.

Pain and the NICU Experience

Infants in neonatal intensive care units (NICUs) may be subjected to an average of 14 painful procedures per day. These procedures, such as heal lancing, suctioning, injections or intubations, are thought to alter infant immune functions, their sensitivity to pain, and reactivity to different stimuli within the NICU environment. In addition, many necessary medical procedures may add to painful experiences that are detected in physiologic changes such as bradycardia, systemic hypotension, or hypoxemia. The preterm neonate thus requires a unique approach to pain management by NICU caregivers who understand both the short-term and the long-term consequences of painful experiences at critical stages of an infant’s development.

NINR-supported scientist Dr. Gayle Page of Johns Hopkins University notes that exposure to painful stimuli produced measureable immunological responses, both short-term and long-term, in neonatal animals.Dr. Page’s findings were part of a growing body of evidence demonstrating that early pain experiences have significant biological and biobehavioral consequences for many at-risk infants.(1-3)

But, how do you measure pain responses in a medically-fragile, preterm infant? Assessment of pain in infants is often based on observing the newborn’s behaviors or monitoring physiological responses such as temperature, blood, pressure, heart rate, and oxygen consumption. Dr. Rosalie O. Mainous at the University of Louisville developed a method to detect and measure physiological responses to pain in premature infants less than 24 hours old taking advantage of technologies readily available in NICUs.

Using cranial Doppler ultrasound and cardiorespiratory monitoring technologies, Dr. Mainous recorded changes to cerebral blood flow and vital signs while the infant experienced a painful ‘heel sticks’ procedure. A balance of blood flow through the brain is important--too much can damage delicate brain tissues while too little can cause tissue death. Dr. Mainous and her colleague Dr. Stephen Looney found that these flow patterns, as measured by peak systolic blood flow, significantly increased following the heel stick. Heart rate, respiratory rate, and oxygen-based vital signs also significantly changed at certain time points following the procedure. In addition, a small subset of subjects in the sample had a distinct blood flow pattern based on simultaneous changes in flow and resistance i.e., when flow velocity to the brain increased, blood flow resistance decreased. This unique pattern may reflect indicators of a risk for intraventricular hemorrhage (IVH), a common injury in infants born at less than 32 weeks’ gestation. These and other studies continue to provide evidence of the complex biobehavioral and physiological responses associated with infant pain. Discovering new ways to both detect and manage pain in premature infants may help to reduce pain-related stress and improve outcomes in these fragile, patient populations.(4)

Pain, Temperament, and Touch

Changes to temperament (the way in which infant’s experience and react to their environments) during NICU care as an indicator of physiological and behavioral pain responses is a growing area of research. Injury, pain, and medical complications, among others, in vulnerable, high-risk premature infants can result in withdrawal, irregular biorhythms, slowness to adapt to changes, distractibility, and overreaction to handling or medical procedures.(5)

In particular, tactile vulnerability (hyperreactivity and defensiveness to touch) may be associated with infant responses to pain or injury. These responses may influence mother-infant interactions and the type and degree of handling provided to the infant during care.

NINR-supported investigators led by Dr. Sandra Weiss at the University of California San Francisco looked at the relationship between painful medical events (e.g., surgery, resuscitation, ventilation assistance, seizures) and the presence of tactile vulnerability in preterm, low birth weight infants during their second week of life.6 The number of medical events experienced by these infants was a primary predictor of the infants who developed hyperarousal and distress from touch during care. Infants with metabolic abnormalities appeared particularly vulnerable to noninvasive or innocuous touch, perhaps because contact can be painful for these infants during medical procedures or handling.(6) 

As the number of premature infants born each year in the United States continues to rise, attention to both behavioral and physiological clues that indicate possible pain, vulnerability to touch, and sensitivity to the NICU environment may lead to fewer painful procedures, better problem identification, and earlier interventions to reduce infant distress.

Getting the Right Amount of Pain Medication When Needed: Children with Sickle Cell Disease

For a child with sickle cell disease (SCD), an acute vaso-occulsive episode can be extremely painful; often requiring admission to a hospital. The unpredictable nature of these frequent painful episodes poses a number of difficult challenges in terms of pain management. For example, while hospital guidelines call for aggressive pain management when SCD children are admitted, there is little standardization in the types of analgesics hospital use, how they are administered, and guidelines for correct dosing schedules.

Dr. Eufemia Jacob and Dr. Brigitta Mueller of Baylor College of Medicine are working to understand how acute painful experiences might contribute to long-term consequences in children with sickle cell disease. Children with SCD, who were admitted to hospital in acute pain, completed a pain assessment tool and rated their own level of pain. Their medical charts were reviewed to determine the frequency, dose, and route of all analgesic medications given throughout their course of stay.

On the day of admission, when pain was often the highest, the most frequent medications given were morphine, kertolac, and diphenhydramine. Other medications included acetaminophen, acetaminophen with codeine, amytriptyline, and hydromorphone. The study found, however, that the administered doses of morphine were in the subtherapeutic to low therapeutic range for 85% of the SCD children. Doses of other medications tended to be in the low therapeutic range as well. Using a tool to quantify the medications used and dose equivalents across the children, the average score for medications prescribed was higher than the average score of medications actually administered, underscoring the finding that these children may be receiving suboptimal pain treatments despite their expression of high levels of pain.(7,8)

These research studies and others conducted by NINR scientists stress the importance of research to help in the discovery of the origins of pediatric pain, the need to understand how procedural experiences and care might be contribute to pain in the young, and the need to find new and improved ways to detect and manage pain and its symptoms in children of all ages.

1 Page GG, Blakely WP, Kim M. The impact of early repeated pain experiences on stress responsiveness and emotionality at maturity in rats. Brain Behav Immun 2005 Jan;19 (1):78-78.

PubMed:  http://www.ncbi.nlm.nih.gov/sites/entrez/15581741

2 Page GG. Are there long-term consequences of pain in newborn or very young infants? J Perinat Educ 2004 Summer; 13(3):10-17. PubMed:  http://www.ncbi.nlm.nih.gov/sites/entrez/17273395 

3 Page GG, Fennelly AM, Littleton-Kearney MT, Ben-Eliyahu S. Male-female difference in the impact of B-aderenoceptor stimulation on resistance to experimental metastasis: Exploring the effects of age and gonadal hormone involvement. J Neuroimmunol 2008, 193(1-2):113-119. PubMed:  http://www.ncbi.nlm.nih.gov/sites/entrez/18037507

4 Mainous RO, Looney S. A pilot study of changes in cerebral blood flow velocity, resistance, and vital signs following a painful stimulus in the premature infant. Adv neonatal Care. 2007 Apr; 7(2):88-104.

PubMed: http://www.ncbi.nlm.nih.gov/sites/entrez/17605449

5 Weiss SJ, John-Seed MS, Wilson P. The temperament of pre-term, low birth weight infants and its potential biological substrates. Res Nurs Health 2004 Dec’27(6):392-402. PubMed:  http://www.ncbi.nlm.nih.gov/sites/entrez/15514956  

6 Weiss SJ, Wilson P. Origins of tactile vulnerability in high-risk infants. Adv Neonatal Care. 2006 Feb; 6(1):25-36.

PubMed:  http://www.ncbi.nlm.nih.gov/sites/entrez/16458248

7 Jacob E, Miaskowski C, Savedra M, Beyer JE, Treadwell M, Styles L. Quantification of analgesic use in children with sickle cell disease. Clinical Journal of Pain. 2007 23(1): 8-14.

PubMed:  http://www.ncbi.nlm.nih.gov/sites/entrez/17277639

8 Jacob E, Mueller BU. Pain experience of children with sickle cell disease who had prolonged hospitalizations for acute painful periods. Pain Medicine 2008 9(1):13-21.

PubMed:  http://www.ncbi.nlm.nih.gov/sites/entrez/18254762

Pathways to Understanding Self-Management Interventions for Chronic Pain

Self-management holds great promise as an intervention approach to treat chronic pain. In self-management programs, the individual patient becomes an active participant in their pain treatment–engaging in active problem-solving, decision-making, developing good use of health resources, and taking actions to manage their pain. Although self-management programs can vary according to the targeted patient population, mode of delivery, or intervention method, they all emphasize education about pain and its consequences, the teaching of strategies to address and cope with pain, and active communication between the patient and health care provider.

Through National Institute of Nursing Research (NINR)-supported research, the implementation of successful self-management programs has reduced many barriers to effective pain management, whether cancer-related pain, arthritis, back pain, or other chronic pain conditions. Individuals who participate in these programs have significantly increased their ability to cope with pain; they report fewer negative responses to their pain symptoms, and they demonstrate better overall management of their painful conditions. In fact, new research suggests that the positive effects of self-management programs might be mediated by a combination of strategies to change how an individual thinks about pain and the actions they take to manage it.

Self-Management of Pain in Older Adults

Persistent pain is a common, often debilitating problem in adults over 65 years, affecting 58-70% of community-dwelling older adults. The most common types of persistent pain in this age group are neuropathic and musculoskeletal pain (e.g., low back pain, osteoarthritis pain, and pain in previous fracture sites). To cope, older adults often rely on the use of numerous pain medications, many which may not work effectively. Other medical and surgical therapies are only moderately helpful and can be associated with significant risks. Finding new strategies for chronic pain management in older adults is thus an important area of research.(1,2) 

NINR-supported researchers led by Dr. Mary Ersek of the Pain and Palliative Care Research Department at the Swedish Medical Center in Seattle have been studying pain-related disability in older Americans and discovering new self-management approaches to treat pain and prevent debilitating functional problems. To evaluate the effectiveness of non-drug and non-surgical strategies to manage persistent pain in older adults, the investigators conducted a randomized, controlled trial of a self-management intervention using two groups of participants: a self-management training group (SMG) compared to an education-only (BOOK) control condition. Older adults (mean age 81.8 years) who experienced persistent, non-cancer pain that limited function were recruited from 43 retirement communities. Each participant was evaluated for level of physical disability, depression, pain intensity, and pain-related interference with daily activities. Following the trial program, the SMG group showed a significant increase in the use of two important strategies to cope with pain: relaxation and the active use of exercise/stretching. While their pain was not alleviated, the findings point to the need for strategies to help seniors manage chronic pain and the benefits of active elder participation in addressing complex issues surrounding their individual pain symptoms.(3)

Self-Management of Cancer Pain

Principal investigator Dr. Sandra Ward from the University of Wisconsin-Madison noticed that cancer patients often under-utilize pain medications due to their concerns about a medication’s side effects or misconceptions about effective ways to manage their pain. Consequently, many cancer patients experience unrelieved pain that impairs their quality of life. Dr. Ward’s research team hypothesized that if these patients were well-informed about their pain symptoms through an individualized education program called ‘RIDcancerPain’ they might become more involved in their own pain management, leading to better adherence to their prescription pain medications and an improved quality of life.

Patients with a diagnosis of metastatic cancer and undergoing treatments at one of two outpatient oncology clinics were randomized into two intervention groups. Group 1 patients received general information about pain through informational pamphlets while Group 2 patients received the one-to-one RIDcancerPain psychoeducational program focusing on their own perceptions of their pain, its causes, treatments, and interventions. Both patient groups received opportunities to discuss issues in a follow-up telephone interview, but in comparing the two approaches, the RIDcancerPain program, through its attention to individual needs and active involvement of patients, was more effective as a pain management strategy. Patients receiving the RIDcancerPain intervention demonstrated greater positive beliefs about the benefits of analgesic use and reported lower ratings of their usual levels of pain. While the program did not eliminate pain, it did seem to result in a reduction in the number of barriers that patients felt existed in effectively managing their pain. Together, these changes might play a role in mediating long-term outcomes of managing the severity of an individual’s pain.(4)

Patient education is a critical part of interventions to help patients experience optimal benefits of a pain management program. RidcancerPain and other self-management tools that focus on meeting an individual’s specific pain needs hold great promise in providing patients useful tools to overcome many barriers to effective pain management. One of these areas may be in the treatment of fibromyalgia.

Self-Management of Pain in Fibromyalgia

Fibromyalgia (FM) is a common, costly, and debilitating syndrome with symptoms that include localized and widespread pain, disrupted sleep, fatigue, joint pain, and other pain syndromes. These symptoms often make it difficult for individuals with FM to exercise. What results is a cycle of pain brought on by deconditioned muscles that are then more likely to experience muscle ‘microtrauma’ following activity. Those FM patients who can tolerate exercise seem to benefit from the activity, reporting a decrease in FM symptoms. Unfortunately, traditional exercise interventions are often geared to the general public rather than on individual self-management of FM-specific pain.(5) 

Dr. Kim Jones and colleagues at the Oregon Health and Science University combined exercise and medication in an effort to create an individualized, self-management intervention for pain associated with FM. The combination of a management program using both exercise and a prescription medication was based on the premise that approximately one-third of FM patients have low levels of certain growth factors which may predispose them to the development of exercise-induced muscle ‘microtrauma’. A drug called pyridostigmine (PYD) has been thought to correct this growth hormone defect.

In the study, women with FM who participated in the combined exercise and PYD program reported improvements in their sleep, anxiety, and overall quality of life. While there were no improvements in pain symptoms between the groups, the women receiving the tailored program did experience improvement in overall activity, without significant exercise-induced pain. These results were supported in a follow-up six-month randomized trial by Dr. Jones and her colleagues demonstrating that combined approaches to pain management may address multiple, yet specific symptoms, e.g., PYD improved anxiety and sleep, while exercise improved fatigue and fitness.(6)

1 Kemp CA, Ersek M, Turner JA. A descriptive study of older adults with persistent pain: use and perceived effectiveness of pain management strategies [ISRCTN11899548]. BMC Geriatr. 2005 Nov 8; 5:12.

PubMed: http://www.ncbi.nlm.nih.gov/pubmed/16277666  

2 Turner JA, Ersek M, Kemp C. Self-efficacy for managing pain is associated with disability, depression, and pain coping among retirement community residents with chronic pain. J Pain. 2005 Jul; 6(7):471-479.

PubMed: http://www.ncbi.nlm.nih.gov/pubmed/15993826 

3  Ersek M, Turner JA, Cain KC, Kemp CA. Results of a randomized controlled trial to examine the efficacy of a chronic pain self-management group for older adults [ISRCTN11899548] .Pain 15 August 2008 138(1):29-40.

PubMed: http://www.ncbi.nlm.nih.gov/pubmed/18086516

4 Ward S, Gunnarsdottir S, Shapiro GR, Donovan H, Serlin RC, Hughes S.  A randomized trial of a representation intervention to decrease cancer pain (RIDcancerPain).  Health Psychology. 2008, (27(1):59-67.

PubMed: http://www.ncbi.nlm.nih.gov/pubmed/18230015

5 Jones KD, Burckhardt CS, Clark SR, Bennett RM, Potempa KM. A randomized controlled trial of muscle strengthening versus flexibility training in fibromyalgia. J Rheumatol. 2002 May; 29(5):1041-1048.

PubMed: http://www.ncbi.nlm.nih.gov/pubmed/12022321

6 Jones KD, Burckhardt CS, Deodhar AA, Perrin NA, Hanson GC, Bennet, RM. A six-month randomized controlled trial of exercise and pyridostigmine in the treatment of fibromyalgia. Arthritis Rheum. 2008 Feb; 58(2):612-622.

PubMed:  http://www.ncbi.nlm.nih.gov/pubmed/18240245