| By Cox, Darcy; Stone, Jerome Abstract: Difficulties with self-injection, including inability to self-inject, are common for individuals taking home-administered injectable medications. In relapsing-remitting multiple sclerosis (MS), all of the currently available disease-modifying medications are injectables marketed for self-injection. Problems with self- injection pose a barrier to treatment adherence for many patients. Clinicians at the University of California, San Francisco (UCSF) Multiple Sclerosis Center have developed a number of strategies to help patients who experience anxiety associated with self- injection. These strategies have been empirically tested and found to be effective and easily implemented by mental health professionals and nurses. This article offers case examples and discussion of the principles of the techniques developed at UCSF to remediate patients' difficulties with self-injection. Nurses are most often the healthcare providers responsible for training MS patients in self-injection and monitoring their compliance. Nurses who are familiar with these tools have the opportunity to have a significant positive impact on patient comfort, confidence, and, ultimately, successful long-term adherence to disease-modifying medications. Most patients dislike injections, particularly self-administered injections. Common reactions include anxiety, fear, avoidance, autonomie reaction, and disgust. In some cases, patients' reactions make it extremely difficult or impossible to receive injections. These patients may meet criteria for the Diagnostic and Statistical Manual of Mental Disorders diagnosis Specific Phobia Blood/ Injection Type (American Psychiatric Association [APA], 1994). This phobia is fairly common, with an estimated prevalence of 7%-22% in the general population (Agras et al., 1969; APA; Bienvenu & Eaton, 1998; Cartwright et al., 1993; Costello, 1982). The diagnosis is generally more common in paediatric patients. Treatment regimens that require more frequent injections are more likely to be associated with injection anxiety (Mohr, Bondewyn, Likosky, Levine, & Goodkin, 2001). In general, injection anxiety decreases over time, with increased exposure to injections in the course of routine immunization and illness and with increased ability to control the circumstances of medical care as an adult. Many adults can receive injections administered by others with minimal difficulty and discomfort, but they experience significant levels of anxiety if they are required to self-inject. This anxiety poses a barrier to treatment for multiple sclerosis (MS), because the patient becomes dependent on others to administer injections. Self-injection allows the patient maximum independence and reduces the risk of missed injections or drug discontinuation due to unreliable injection assistance. There are four self-injectable treatments for relapsing- remitting MS (RRMS) that slow disease progression. Interferon beta- lb (IFN(Mb; Betaseron) and glatiramer acetate (Copaxone) are approved for subcutaneous (SC) administration. Interferon beta-la (IFNfMa) is approved for SC administration (Rebif 22 meg or 44 meg ) and intramuscular (IM) administration (Avonex 30 meg); (Durelli et al., 2002; Jacobs et al., 1996; Johnson et al., 1995; IFNB Multiple Sclerosis Study Group, 1993). These medications require injection daily (glatiramer), every other day (IFNfMb), three times a week (IFN(Ma SC), or weekly (IFNfMa IM). Adults who are unable to self-inject may be at risk for poor treatment adherence. In a study of patients initiating IM IFNfMa treatment, half experienced self-injection anxiety sufficient to prevent self-injection. Self-injection anxiety and a belief that one could not self-inject were the strongest predictor of drug discontinuation at 6 months (Mohr et al, 2001). Because reduced adherence to therapy can lead to reduced efficacy of treatment, there is a need to manage self-injection anxiety in patients with MS. At the University of California, San Francisco (UCSF) Multiple Sclerosis Center, we encounter numerous patients who present with self-injection difficulties. Some report self-injection anxiety at the initiation of treatment. Others report that they were able to self-inject successfully for months or years before they developed anxiety. Such difficulties have been observed regardless of the type of disease-modifying treatment. Multiple factors can contribute to the inability to self-inject. Many patients are misinformed about the risks of self-injection and believe it to be unsafe or even potentially life-threatening. Others are misinformed about how best to manage injection pain and side effects. Many patients experience autonomie reaction, including vasovagal responses, and misinterpret these sensations as dangerous. We also found that many patients have distorted beliefs about the injection and the meaning of the injection in their lives. Specifically, patients begin to consider the injection to be a burden associated with their disease, rather than the way to best manage their disease. For these patients, disconnecting the experience of the injection from the experience of living with MS is often necessary to allow self-injection. Almost all patients with self-injection difficulties reported some feeling or belief that self-injecting means "I really have MS" or "I'm allowing the MS greater control of my life." Current RRMS treatment recommendations strongly encourage that treatment be started immediately following definitive diagnosis (Comi et al., 2001; Jacobs et al, 2000; Kinkel et al., 2004). Therefore, many patients who start injectable therapy are experiencing few or no MS symptoms. As such, patients often feel injections are a reminder of the disease. Patients need help accepting their diagnosis and understanding the need for treatment. This help is crucial for long-term adherence to medication, which appears to be crucial for good longterm outcome. At UCSF, we developed a six-session cognitive behavioral treatment for self-injection anxiety. This model has been tested and found to be effective when either psychologists or nurses are providers. The trials have been described elsewhere (Cox, Mohr, & Epstein, 2004; Mohr, Cox, Epstein, & Bondewyn, 2002, 2005). However, we think additional case examples that demonstrate specific principles used in the treatment of selfinjection anxiety may prove useful for providers who are considering implementing this method. Our model and examples were developed for patients with RRMS. However, these principles can be applied to patients on any injectable medication who have difficulty selfinjecting. Nurses are responsible for most self-injection training, and, in many settings, nurses play a major role in managing difficulties with adherence. It is our hope that the principles we have developed will prove useful for nurses who care for patients who must self- inject and will help patients and their care providers maintain strong adherence to necessary therapies. Autonomie Reaction, the Anxiety Response, and Development of Phobic Symptoms Autonomic reaction refers to a number of physical changes, including increased respiratory rate or hyperventilation, palpitations, flushing, and gastrointestinal disturbance, which most frequently occur in response to anxiety-provoking or potentially dangerous stimuli. These physiologic reflexes depend greatly on cognitive interpretation. For example, people who enjoy riding roller coasters experience these physiologic changes as they ride but interpret them as "excitement" or "an adrenaline rush." People who have self-injection anxiety and phobia interpret these sensations, when they occur before injection, as a cue that something dangerous is about to happen. This feeling increases their physiologic arousal level, which produces an even stronger emotional feeling that something bad is going to happen. The result is a spiral of increasing experienced anxiety and physiologic arousal. The physiologic responses and the experience of anxiety frequently are reduced only when the patient avoids self-injecting. Thus, the experience of reducing autonomie reaction through avoidance reinforces avoidance: "I felt terrified and awful, so I didn't inject.... If I try to inject again, I will only feel even more terrified and awful." The experience of autonomie reaction both punishes attempts to self-inject and reinforces avoidance of injecting. This reinforcement makes it progressively more unlikely that the patient will inject or persevere in attempts to inject. Even patients who are well-educated about the safety of injections and committed to their treatment may experience an autonomie reaction. It is important to help these patients understand that physiologic sensations are not, in fact, a cue that something dangerous is about to happen. Treatment of Self-Injection Anxiety Accurate and Timely Patient Education All pharmaceutical companies that market injectable medications for MS provide injection-training services through home health nurses. The quality of these services varies a great deal, and patients may have received incomplete or inaccurate information during training. We encourage these companies to continue to improve their services but also recognize the difficulties associated with providing services nationwide. We acknowledge that \nurses who serve MS patients must also educate patients. Nurses who work with patients with self-injection anxiety should begin by ensuring that the patient is well educated about how to prepare the injection and how to inject safely and comfortably. In many cases, ensuring that the patient is well-prepared before self- injection is attempted can prevent the development of self- injection anxiety. It is helpful to gauge patient understanding by asking the patient to repeat what he or she has just learned. The act of teaching through repetition enhances patient retention and can improve patient confidence. The focus of training at UCSF is on maintaining good hygiene, understanding safe injection techniques, and increasing relaxation and confidence. The authors found that patients develop several different strategies for the injection. Some insert the needle quickly, whereas others insert the needle slowly, perhaps taking 30 seconds or longer to reach the muscle, for an BVI injection. Although injecting this slowly is certainly not taught in nursing school and may increase pain in patients who increase muscle tension in response to inserting the needle, there is no hygienic reason to avoid it. One of the authors experimented with this technique on himself and found it to be remarkably comfortable. However, the other author was unable to remain sufficiently relaxed when attempting this technique and found it to be significantly more painful. In short, it is important to focus on hygiene and the individual patient's experience of relaxation and comfort rather than on preconceived notions of the right way to self-inject. We frequently offer multiple strategies and allow patients to experiment to find what works best for them. In addition to training patients in injection techniques, we directly and repeatedly reassure patients that self-injection is safe. We also proactively work to reassure patients that self- injection is not damaging or potentially fatal. Allaying Fears Many patients erroneously believe that injections have the potential to be damaging. Common concerns include fear of injecting an air bubble and causing an embolism, hitting a vein, hitting a bone, or damaging muscle with an IM injection. Many patients focus on the air bubble and mistakenly believe that if they inject any air whatsoever, they will experience an embolism. This belief can lead to increased anxiety, reduced doses, and increased pain, as patients attempt to remove air bubbles that do not need to be removed and adopt other compensatory strategies that may worsen the problem. In our clinic, we treated a male in his thirties with moderate- to-severe anxiety about self-injection. One of his coping mechanisms was to inject extremely quickly while looking away, pressing the needle hard into a tense muscle, which caused significant pain. On specific questioning about his self-injection beliefs, he revealed his belief that injecting any amount of air could kill him. He therefore injected very quickly with his eyes closed as an attempt to "get it over with." He reported that he almost felt as if he were playing Russian roulette. After receiving education on safe self- injection, including a lengthy question-and-answer session, he relaxed and self-injected with little difficulty. We often discuss with our patients the difference between hurting and harming. Various aspects of the procedure can lead to hurting (i.e., pain). Medication recently removed from the refrigerator, poor injection technique, poor site selection and rotation, and muscle tension in IM injection can and will increase the subjective experience of pain. However, none of these cause harm (i.e., lasting damage to one's body). If carried out with a reasonable understanding of hygiene, site selection, and technique, injections are not dangerous. For some patients, fear of harm arises from either a lack of information or misinformation. When accurate information is presented, fear subsides. For other patients, including some with medical backgrounds, a fear may be acknowledged as irrational. For example, the patient knows it is not possible to hit the femur while injecting IM into the thigh but, nonetheless, has a persistent image of doing so while injecting. Cognitive reframing may be useful for these patients. Cognitive Reframing Cognitive reframing refers to the examination of one's specific thoughts to determine whether the thoughts are accurate or helpful in the given situation and to then modify those thoughts to make them more accurate or useful. This skill can be applied in a number of ways to manage self-injection anxiety. For example, patients can learn to label autonomic reaction as a collection of physical symptoms rather than to assume that the physical reactions are indicative of impending danger. Patients can learn to change their automatic thoughts in response to increased heart rate, respiration, and muscle tension from "something bad is going to happen" to "I am experiencing autonomie reaction symptoms; I need to practice relaxation." Patients also can use cognitive reframing to support accurate beliefs about the safety of self-injecting. Many patients also find that thoughts about having a chronic illness can pose a barrier to successful self-injection. Such thoughts could be controlled with cognitive reframing. For example, thoughts such as "the injections increase the burden of my disease" might be changed to "injecting helps me maintain my health for the future" with the help of cognitive reframing. One patient treated at UCSF was a woman in her late twenties who was very successful, both professionally and athletically. She stated that her greatest fear about having MS was "I'm going to end up in a wheelchair." She did not initiate treatment at the time of diagnosis and did so only after having experienced a second exacerbation. She responded quickly to education about self- injection technique but experienced fear, anger, and disgust about self-injecting. When questioned about her beliefs regarding the medication and the disease, she said, "I haven't succeeded in being disease free because I have to start on treatment, and failure means I'm going to end up in a wheelchair." After further questioning about her beliefs and thought processes, she revealed that when she was initially diagnosed, the neurologist told her she had "benign MS" and gave her the option to either begin treatment or "wait and see." The patient then "tried to forget [she] had MS" and did not educate herself about the disease or examine her thoughts and feelings about her condition. Instead, she fixated on the belief that her disease was benign and that any further disease activity would signify a change in her disease state from benign to malignant. When she experienced a second exacerbation, she interpreted the need for treatment as a sign that her disease was worsening and inevitably would rapidly progress to a high level of physical disability. Cognitive refraining was used to help shift her focus away from her fear of physical disability and toward the concrete steps she could take to reduce future disability. While acknowledging that no one, including the neurologist, nurse, or herself, could predict what the future might hold and that there was a risk of disability, we discussed both the danger of focusing entirely on the risk and the benefit of taking a broader view of what it means to live with MS. She was encouraged to focus on her strengths and to equip herself with knowledge about the disease and its treatment. Although she was already quite active, with a healthy diet and lifestyle, she committed herself to managing her health, increasing her strength and flexibility, and reducing stress even further. She began to view injections as a proactive step she could take to reduce future disability rather than as a sign that she had "failed at having benign MS and must therefore have really bad MS." After meeting other individuals with MS, she began to understand the range of outcomes in the disease and the ways medications can reduce future disability. As a result, she was able to successfully self-inject and her overall adjustment to her diagnosis improved, as did her mood and quality of life. Another patient presented to the clinic when she developed self- injection phobia after several months of successful self- injections. She reported that when she had started injectable treatment, her neurologist had told her, "Don't worry, in a year there will be something else." She reported that she gave herself injections without too much difficulty for the first 10 months, but as it became increasingly apparent that there would be no new treatments available, she started to miss injections. By the end of the year, she had stopped treatment entirely. She reported that she thought "I did my 12 months," and said, "I used up my ability to talk myself into it." The patient had experienced a number of pain-free self- injections and had no problems with technique or fear of harm. Therefore, cognitive refraining needed to focus on the meaning of the illness itself and the treatment. When identifying her thoughts about treatment, she reported that when she was diagnosed, she believed that injections would be a stopgap measure until a new treatment was available, which would not require selfinjection and would result in total disease remission. She reported that she needed to accept the thought that "MS is something [she was] going to have for the long term" and that no treatment would "save [her] from MS." Managing Vasovagal Response Some patients with self-injection anxiety also report a history of vasovagal response to injection. A vasovagal response involves a brief episode of bradycardia and hypotension, either immediately preceding or concurrent with the injection or injection attempt. It may result in feelings of faintness or dizziness, pallor, queasiness, d\epersonalization, and ringing in the ears. It is estimated that 25%-37% of people who meet criteria for the diagnosis of blood-injection-injury phobia experience a vasovagal reaction at least once in response to injection (Antony, Brown, & Barlow, 1997; De Jongh et al., 1998; Kleinknecht, Thorndiker, & Walls, 1996). The percentage of patients who need to self-inject and experience such reactions is unknown. However, for those who have had this experience, anticipatory fear of the vasovagal response also can pose a barrier to successful injection. Relaxation training and graded exposure are useful techniques for patients with self-injection anxiety who have autonomic reaction responses to injections. Patients learn deep muscle relaxation and controlled breathing techniques that prevent hyperventilation and reduce other autonomic reaction symptoms. After patients have mastered these techniques, they are able to move forward with graded exposure to different aspects of the self-injection process. In this way, patients may be able to incrementally increase their comfort and level of self-efficacy (i.e., confidence in themselves) until they are able to attempt self-injection. For patients who do not benefit from relaxation training, other techniques are available to manage vasovagal responses. The simplest is the maintenance of muscle tension, which prevents hypotension. With SC injection, hypotension can be easily managed by performing jumping jacks or any other brief, vigorous exercise the patient is able to perform. With IM injection, it is best to find an exercise that will not tense the muscle group into which he or she will be injecting. Patients with severe vasovagal responses may benefit from a low-dose betablocker before attempting self-injection. Vasovagal responses are almost always quite brief and benign, although there have been case reports of ventricular fibrillation, myocardial infarction, cerebral infarction, or severe vascular disease following exposure to injection or venipuncture (Hamilton, 1995). Dealing with Feelings of Disgust For some people, injections are not simply frightening: They are disgusting. The combination of fear and disgust appears to contribute to worsened phobic symptoms. People who merely fear injections seem to respond better to treatment than those who find injections disgusting as well. Disgust can be managed by normalizing the experience and, in some cases, by applying cognitive refraining techniques to the autonomie experience of disgust. Managing Pain and Side Effects Obviously, minimizing injection pain, injection-site pain, and unwanted side effects from medications will make self-injecting easier and less unpleasant. It is essential to titrate interferons, ensure that medications are at room temperature when injected, and select and rotate the injection site appropriately. For IM injections, it is important to be aware of how MS-related spasticity can increase pain and to work with patients to select sites that are not tense. Injection-site reactions are a significant problem for all of the SC-injected MS medications. Educating patients regarding the common occurrence of injection-site reactions with SC injections and teaching them to identify serious reactions and to seek rapid treatment for them can reduce anxiety and help maintain self- injection. Many people believe that self-injecting will hurt more than receiving the injection from another person. This concern is seen even in individuals who receive injections from others without undue difficulty. Frequently, patients feel that self-injection will be more painful because they are not confident that they have mastered safe self-injection technique. Good education and reassurance can be useful here. It is important to remember that, for some patients, anxiety can increase the experience of pain and that for others, significant anxiety reduces the experience of pain. For some, the anxiety they experience before self-injecting is so great that they enter a mildly dissociative state and may not experience any pain at all. Summary Self-injection anxiety is a fairly common problem among patients with MS. Fortunately, self-injection anxiety can be reduced with brief treatment in most cases. The treatment strategies we have developed have been validated in a number of small clinical trials (Cox et al., 2004; Mohr et al., 2002, 2005) and are available online without charge to both patients and their providers. The clinicians at the UCSF MS Center who have provided treatment for self-injection anxiety have found it to be a particularly rewarding clinical activity. We enjoy celebrating patient successes and helping patients learn to inject with confidence rather than experience fear and failure. References Agras, S., Sylvester, D., & Oliveau, D. (1969). The epidemiology of common fears and phobia. Comprehensive Psychiatry, 10(2), 151- 156. American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychiatric Association. Antony, M. M., Brown.T.A., & Barlow, D. H. (1997). Heterogeneity among specific phobia types in DSM-IV. Behaviour Research and Therapy, 35, 1089-1100. Bienvenu, O. J., & Eaton, W. W. 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M., Richert, J. R., Salazar, A. M., et al. (1996). Intramuscular interferon beta-la for disease progression in relapsing multiple sclerosis. Annals of Neurology, 39(5), 285-294. Johnson, K. R, Brooks, B. R., Cohen, J.A., Ford, C. C, Goldstein, J., Lisak, R. R, et al. (1995). Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: Results of a phase III multicenter, double-blind, placebo- controlled trial. Neurology, 45, 1268-1276. Kinkel, R. P., Kollman, C., Glassman.A., et al. (2004). Interferon beta-1a (Avonex) delays the onset of clinically definite MS over 5 years of treatment: Results from CHAMPIONS study [Abstract]. Neurology, 62(Suppl. 5),A261. Kleinknecht, R. A., Thorndike, R. M., & Walls, M. M. (1996). Factorial dimensions and correlates of blood, injury, injection and related medical fears: Cross validation of the Medical Fear Survey. Behaviour Research and Therapy, 34(4), 323-331. Mohr, D. C., Boudewyn, A. C., Likosky, W., Levine, E., & Goodkin, D. E. (2001). Injectable medication for the treatment of multiple sclerosis: The influence of expectations and injection anxiety on adherence and ability to self-inject. Annals of Behavioral Medicine, 23(2), 125-132. Mohr, D. C, Cox, D., Epstein, L, & Boudewyn, A. (2002). Teaching patients to self-inject: Treating injection anxiety and phobia in patients prescribed injectable medications. Journal of Behavior Therapy and Experimental Psychology, 33(1), 39-47. Mohr, D. C., Cox, D., & Merluzzi, N. (2005). Self-injection anxiety training: Successful treatment for patients unable to self- inject injectable medications. Multiple Sclerosis, 11(2), 182-185. Jerome Stone, RN, is manager of integrative care at Mercy Hospital in Portland, ME. Copyright 2006 American Association of Neuroscience Nurses 0047- 2606/06/3803/00167$5.00 Copyright American Association of Neurosurgical Nurses Jun 2006 (c) 2006 Journal of Neuroscience Nursing. 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Disease Modifying Drugs are a group of compounds which alter the progression of MS. They have been shown to reduce the frequency and severity of relapses and slow the development of disability in some people.