The Endorphin System

The endorphin system is the neuroendocrine system responsible for the modulation of pain and stress responses. It consists of a wide variety of poorly defined neurons and neuroendocrine cells that produce three main types of opioids: beta-endorphins, enkephalins, and dynorphins. These opioids function as neuromodulators by stimulating opioid receptors.

After a person has responded to a painful or stressful stimulus, the normal function of the endorphin system is to decrease the response to the pain and stress. This system is dynamic and can increase or decrease its effect to promote the appropriate response to a painful or stressful event. Like other neuroendocrine systems, it contains a feedback loop, and high levels of endorphins inhibit the further stimulation of the system. As a result of this feedback loop, when a pain signal is prolonged or intense or in the setting of exogenous opioid therapy, the system can become less responsive to pain, and less effective in controlling the pain response.

Endogenous opioid system responses differ between the sexes,[53, 67] accounting for some of the variation in responses to pain and pain treatments. Differences in the endorphin system would lead to differences in the response to pain after its initial perception, as has been found in many pain studies. This could account for differences in the response to pain over time, and in differences in the response to therapy.

Clinical Evaluation

The degree to which a person experiences pain is a complex and subjective interaction between the perception of the physical stimulus and the patient’s cognitive and emotional state. The experience of pain is not directly determined by the extent of a person’s injury, and patients with identical injuries often display completely different amounts of pain.[9] This has frustrated attempts to uniformly recommend specific pain therapies based solely on the nature of the patient’s illness of injury. The treatment must be based on the subjective assessment of the patient’s pain.

The assessment of pain depends on the person’s ability to communicate the nature of the pain to the physician, and the physician’s ability to interpret the communication. No objective test or physiologic index measures pain reliably. Objective observations, such as hypertension, diaphoresis, or tachycardia, do not correlate well with the degree of pain present.[6, 68, 69] This leaves the assessment of pain dependent on communication, interpretation, and empathy, making the assessment of pain particularly vulnerable to the effects of a patient’s gender[69–76] and a provider’s gender.[77] Other factors, such as anxiety, which correlate well with the degree of pain present,[17] are just as difficult to measure as pain due to their subjective nature.[8, 22, 77–82]

Pain Measurement

Pain is typically measured using numeric rating scales, using a wide range of variations of a verbal 0 to 10 score ranking pain from none to worst imaginable.[83] Visual analogue scales, usually consisting of a 10-cm straight line with anchors at either extreme are frequently used in research to provide continuous data for analysis. These scales offer little practical advantage over verbal reports in the clinical setting.[70, 74, 84–86] Routine pain assessment encourages clinicians to communicate with patients to assess their pain and to evaluate responses to analgesic intervention attempts.[25, 87]

Whichever pain scale is used, it essentially serves as a communication tool between the patient and the physician to describe pain. The score a patient uses to describe pain may have as much to do with how the patient desires the health care provider(s) to respond to the pain complaint as it does a description of the pain relative to previous experiences. As a patient undergoes treatment, changes in the pain scores may represent a number of factors including satisfaction from analgesic interventions, a desire for further treatment, and actual changes in experienced pain. Generally, the significance of a change is pain in related more to the percentage change in a score than its absolute change.[88]

Differences in pain scale scores for identical painful stimuli by sex have been reported, with higher scores assigned to the stimuli by women.[61] Differences between the measurement of changes in pain scales with changes in described pain by sex have been reported as well,[20] with a larger change in pain scales associated with a change in verbally described pain for women than for men. The minimum clinically significant difference in pain scores or the change in score associated with a verbal description of a difference in pain was not detected between genders.[21, 88] Differences in the way a patient expresses pain, changes in pain, and desire for intervention that are not detected by the measurement tool are lost if that is the primary method of pain assessment. The active assessment of pain to determine the precision of a pain score is necessary for the score to be useful in clinical decision making. The measurement tools, however, provide a reference point for both the patient and the provider during repeat assessments. Available studies indicate that pain scores in women are more likely to vary relative to verbally described pain, but they similarly describe the presence, absence, or changes in pain. Standardizing the assessments and then using the information in conjunction with other historical information are likely to increase the accuracy of these scales and decrease differences in pain treatment due to assessment.[8]

The accurate diagnosis of the underlying cause of pain is the primary concern of the treating physician, but for the patient it is often secondary to the desire for adequate pain relief. The assessment of pain is closely related to the effectiveness of pain treatment, but an accurate interpretation of the degree of physiologic stimulation based on a patient’s pain assessment is an important piece of information in the determination of the cause of the pain. If a patient has focal guarding and rebound tenderness in the right lower quadrant and appears in pain, it does not matter if the patient reports the pain score as a 2/10 or a 10/10, the patient will likely be evaluated for appendicitis. The patient with the higher pain score, however, may be expressing the desire for intervention by conveying that the pain is distressing, whereas the patient with the lower pain score may be attempting to downplay the pain to avoid the necessity of treatment. Understanding and accounting for pain scales in the context of gender requires recognition of these scales as communication tools rather than as a measurement of physiologic status.

Acute Versus Chronic Pain

Chronic pain can be described as any pain that persists after the tissue injury initially associated with the pain has healed as much as expected. This pain can be from injuries that are not expected to heal (e.g., degenerative joint disease) or from pain transmission system dysfunction (neurogenic pain). Chronic pain conditions are more frequently reported among women than men.[89] Chronic pain has also been associated with reported pain intensity and the adequacy of initial pain treatment. Women report higher degrees of pain than men and are more likely to be undertreated, accounting for some portion of the increased prevalence of chronic pain among women. Other factors are likely not yet defined, such as differences in the endorphin system responsiveness, differences in neuromodulation of pain signals, and differences in the effectiveness of treatments, that remain to be defined.

Treatment

The optimal current approach for treating moderate to severe acute pain is to titrate IV opioid analgesics effective levels for each individual patient.[1, 2] Research indicating that there are sex differences in pain and analgesia hold out the promise that pain treatment can be guided by a patient’s sex.

Clinical studies of sex differences in response to μ-opioid agonists have had mixed results. Clinical studies have shown that gender does not appear to effect the likelihood of receiving opioids.[90]Clinical studies have also demonstrated that morphine is more effective in women than men, both in terms of the quantity needed to achieve pain relief with patient controlled analgesia (PCA)[91] and in terms of the analgesic effect of a given dose. A meta-analysis performed in 2010, however, found no overall sex differences in response to IV μ-opioid analgesics. There was substantial heterogeneity of findings, with about equal numbers of studies indicating superior female response, male response, and equal response. There has been evidence of greater efficacy of mixed-action opioid agonist-antagonists (pentazocine, nalbuphine, and butorphanol) in women than men in clinical studies, but no experimental studies have been done to determine the nature of this. In contrast to efficacy, evidence is more supportive that women experience more adverse responses to IV opioids than men, particularly nausea and vomiting and affective disorders associated with opioid use.[12, 18, 63–66, 89, 92–94]

Opioids are commonly used for the treatment of pain. Two percent of the US adult population uses some form of opioid each month.[95] Of these, women are more likely to be regular as well as long-term users.[96, 97] While most opioid prescriptions written for patients reporting pain are appropriate, patients seeking opioid analgesics for nonmedical use are common and represent a risk when pain is treated.[98] Data from the US DEA in 2012 showed that the annual retail sales of prescription opioids for nonmalignant pain have increased sevenfold between 1997 and 2006. The number of fatal overdoses from prescription opioids has also quadrupled during this period, exceeding those from cocaine or heroin and predominantly involves men. The estimated annual cost of prescription opioid abuse in the United States is $11 billion.[97]

The relationship between sex and vulnerability to opioids is therefore important to understand. Data show that women progress from use to dependence more quickly than men, suffer more severe emotional and physical consequences of opioid use as compared to men, and yet underutilize rehabilitation options. In addition, more women are prescribed opioids, have higher dosages prescribed relative to their body weight, and are more likely to have multiple and overlapping prescriptions, putting them at risk of abuse.[99] Both the higher risk of progression to dependence in women and the higher risk of fatal overdose in men must be accounted for in decisions about opioid therapy, especially in patients who appear at risk of dependence.

Stabilizing Secondary Pain Factors

The psychological response to acute pain depends on both the social and cultural context in which the pain occurs, the person’s psychological predispositions, and the current health of the individual experiencing the pain.[100] Evidence from a variety of sources suggests that adverse acute psychological responses to pain, such as high levels of anxiety, distress, and depression, vary with gender.[101] Anxiety has been shown to be associated with pain to a greater degree in women than men.[17] Acute psychological responses to pain are important not only because they facilitate the severity of acute pain but also because they may affect risk of progression to chronic pain.[102–104]

Psychological responses to pain represent potential targets for intervention. Decreasing adverse psychological responses to pain will typically result in decreased reported pain and likely result in better pain relief over the course of an illness or injury. The interventions and treatments that are most effective in limiting these responses are likely to differ by gender.[105–108] As part of the effective treatment of pain, adverse psychological responses should be addressed. Interventions can range from patient education and reassurance and addressing fears about future pain to the symptom-targeted use of sedatives and antipsychotics. Controlling the psychological response to acute pain can be effective for both acute pain and the improvement of long-term outcomes.[106, 109]

Follow-Up and Prognosis of Disease

A large number of ED patients have underlying chronic pain syndromes, which are common in the US population, with rates as high as 40% noted [2]. The key step to the prevention of chronic pain appears to be the adequate treatment of acute pain. Acute pain usually occurs in response to tissue injury and resolves when the injury heals. It serves an adaptive purpose in that it stimulates protection of the injured area, the request for help, avoidance of future similar injuries, and increased blood pressure and respirations. As the injury heals, these adaptive purposes become maladaptive, as limited movement causes a decreasing range of motion, and pain facilitation can become so pronounced that the patient develops pain from otherwise non-painful stimuli.

It can be difficult to determine at what point pain changes from adaptive to maladaptive, or from acute to chronic. Acute and chronic pain call for different treatment approaches, both in terms of the approach to the patient and to the medications used. The maladaptive components of chronic pain can push patients toward behaviors that can hinder their recovery (lack of abnormal use of painful extremities, inactivity) and impact their mood, social interactions, and lifestyle. These issues must be addressed simultaneously with the physical perception of pain to blunt the negative impact of the pain on the patient. In terms of medical therapy, the principal difference between acute and chronic pain is that it cannot be assumed that chronic pain will resolve; therefore, sustainable treatment regimens with manageable side effects and negative impact should be selected.

Discussion

It has become increasingly apparent that women suffer a disproportionate amount of pain compared to men. A growing number of studies have suggested a variety of causes for this sex difference, on both a physiologic and a psychosocial basis. Many studies have demonstrated that the sexual differentiation of pain appears to occur at the same time as the sexual differentiation in puberty, implicating gonadal steroid hormones as important parts of this differentiation. Because these hormones affect the function and development of the nervous, immune, skeletal, and cardiovascular systems, the effects are complex, multifaceted, and still largely undefined.[110]

One of the great challenges we face in trying to determine the place of sex and gender in the treatment of pain is that our assessment of pain remains subjective. A person expresses his or her suffering from pain according to learned behaviors and in accordance with the perceived role of medical care in the social milieu. We do not have an objective measure of pain and therefore must rely on physician assessment to attempt to measure it. The expression of pain is a combination of multiple factors; the physical stimuli, the threshold at which the stimuli are detected as pain, the degree to which the detected pain causes suffering to the individual, and the way in which that person expresses the suffering to observers, and finally the way those expressions are interpreted by the observers. Each of these factors is likely to be affected by the person’s gender. These effects are likely a combination of both the effect of external gender roles and physiologic differences in the pain expression system. We are as yet unable to determine which of these is affecting these differences, and which is more important at what level of pain.

We do not yet have sufficient evidence on gender differences in pain detection thresholds and pain severity to accurately improve diagnosis and treatment in the clinical setting. It seems likely that the simplest step to improve the accurate assessment of pain is to measure it accurately and with a system that is robust to both differences in the detection of pain and the expression of pain. An accurate measurement would be robust to differences in threshold, since the total degree of suffering would be accounted for by an accurate pain measurement without regard to the degree of stimuli and its relative effect on the individual. The challenge is to employ pain measurement systems that accurately detect the degree of suffering an individual faces and any changes that occur over time and with intervention.

Accurate pain measurement requires appreciation of the effect of gender on the expression of pain. Although we do not have accurate information on the effects of gender on pain measurement, it is not a stretch to assume that gender will affect the way patients express their pain to another person. It is likely that the simple statement of a patient-derived pain rating will not take this into account, and that a pain score on a typical patient-derived 10-point scale could not be universally applied between men and women as equivalent. When a patient expresses pain, however, it can be assumed that he or she wants treatment. In using a pain measurement device, we need to pay more attention to the changes in the measurement rather than the degree of the measurement. For example, if a woman and a man with identical injuries present with pain, they would likely have different initial reported pain levels. If the women reports her pain is an “8” and the man reports a “6,” it does not mean they have different levels of pain. It only means that both patients are not at zero and have given us a number that represents that they probably expect us to appreciate that they are in pain. If we give these two patients 0.1 mg/kg of morphine and then ask them to give us a new number, if the man has a score that goes to “3” and the woman has a score than goes to “4,” they have both had their pain report improve by one-half and have probably had similar responses to the pain medication. If one patient’s score went to 1 or 0, we can assume that patient perceives the treatment as adequate. If one patient’s score only decreases by one point, does not change, or increases, the patient is expressing the need for more treatment and communicating that the treatment was not sufficient and that more therapy is expected. The actual values are not the principal determining factor in how much therapy is needed but rather the effect of the therapy given on the initial report. This sort of approach enables us to communicate in a fashion that allows for the inaccuracies of our current pain medication practices and avoids treatment failures, in terms of both undertreatment and overtreatment due to the inaccurate assessment of pain.

Conclusion

Men and women exhibit differences in measured pain and the response to pain treatment. We do not know the relative important of pain detection, pain expression, or pain measurement in differences in pain report, but by appreciating that such differences exist, we can implement more precise and accurate assessments and more effective therapy.

Case Conclusion

The presented case demonstrated many of the common pitfalls of pain management without the benefit of focus from gender differences in pain assessment and treatment. This patient’s presentation, with tachycardia, a pain score of nine, and associated anxiety, exhibits characteristics of acute pain presentation more pronounced in women than in men. The patient had an IV placed and morphine titrated appropriately with adequate relief of pain and then developed nausea, which is also more common in women than men. The patient then developed hypoxia 15 minutes after the dose. Opioids are more efficacious in women than men, and the combination of this with the higher pain report in this case resulted in a large bolus being given. In addition, much of the effect of the first 0.1 mg/kg of morphine is on a patient’s cognitive and emotional state, and it is likely here that the initial dose of morphine had a larger effect on the patient’s anxiety than the underlying pain, resulting in the second dose having a more pronounced effect than the first because of the absence of underlying agitation from anxiety.

After the patient recovered from the large bolus, further treatment was withheld during splinting to avoid further complications. A better approach would be to give a smaller dose than the initial bolus, accounting for the pronounced effect but not limiting analgesia. The splinting procedure was started without further treatment, resulting in agitation and pain on the patient’s part. Subsequent attempts to treat required multiple doses of morphine that had limited success in relieving pain relative to if adequate analgesia had been given prior to the splinting procedure. The patient then developed vomiting due to the large doses of morphine, which further complicated her care and led to the her being discharged without adequate pain relief.

This case demonstrates the complications and complexity of pain care, and that simply initiating treatment does not ensure adequate pain relief. This patient had poor pain relief despite aggressive and timely initial morphine dosing. Focusing on what we know about gender in this case would have improved the care. Knowing that opioids have increased efficacy in women and that pain and anxiety can be more common in women may have led to more accurate assessment of the patient’s initial pain and more precise decision on the morphine dose. Understanding that the opioids effect can be more pronounced in women would have made it clearer that initial overmedication was due to the size of the dose rather than a predisposition to complications from opioids, which may have allowed for adequate pain medication for the splinting procedure. Adequate pain relief for the splinting procedure would have resulted in less subsequent need for opioids, limiting the degree of nausea the patient experienced and its associated complication of the patient’s ongoing pain management.

This case exemplified the notion that the key to the management of pain is not the therapy chosen, but the accuracy of the assessment of pain, both initially and in response to therapy. Understanding differences associated with gender are central to the accuracy of pain assessments and the effective treatment of pain.