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Available at: <http://www.who.int/gender/whatisgender/en/> (accessed 23 Febr uary 2012). CHAPTER 5 Prevention of the development and maintenance of pediatric chronic pain and disab ility M. Gabrielle Pag , Anna Huguet , and Joel Katz Summary Understanding the predisposing factors that confer a greater risk of developing chr onic pain is an essential step in pain prevention and management. Th is chapter focuses on current theoretical mod- els that can inform prevention of pediatric pain and disability. W e review the literature on known risk/protective factors, markers, correlates, and prognost ic factors for the transition to chronic pain and disability across a variety of pain condi tions. We distinguish between primary, secondary, and tertiary levels of pain prevention an d discuss the clinical implications of this distinction. pain. We defi ne and identify risk/protective factors, predictors, correlates, markers, and prognostic factors across pain conditions, describe three types of pain prevention, review current theoretical models of the development and persistence of pain, and describe preven tion strategies associated with identifi ed correlates, markers, risk/protective, and progn ostic factors. Correlated factors, risk/protective factors, markers, and prognostic factors Preventing ped iatric pain necessitates the identifi cation of risk and protective factors from which risk levels for a child to develop pain can be determined. It also requires the identifi cation of prognostic factors to better understand a child \200\231s probability of recovering fro m a chronic pain state. A risk factor is defi ned as a \200\230measurable characterization of each subject in a specifi ed population that precedes the outcome of interest and can b e used to divide the population into \200 high-risk and \200 low-risk groups \200\231 ( Kraemer et al., 1997, p. 338). Th e temporal crite- rion of precedence is essential for a v ariable to qualify as a risk factor; otherwise it is a correlate. Similarly, a protective f actor predicts a lower risk of the outcome (i.e. it protects against the risk). Risk and pr otec- tive factors are both called predictors (i.e. without reference to sign). Predictors that cannot be modifi ed are referred to as fi xed markers (e.g. sex, race; Kraemer et al., 1997). A prognostic factor is a variable that provides information about the chances of re covery from, or recurrence of, a disease or condition. Th us, a risk or protective factor p redicts the chances of developing or contracting a disease, whereas a prognostic factor pre dicts the outcome of a disease (recovery or recur- rence once the disease has developed; La upacis et al., 1994). Introduction Estimates of pediatric chronic pain (i.e. pain that continues past the usual t issue healing time \200\224typically 3 months) range between 15% and 30% (Bandell-Hoekstra et al., 2001; Perquin et al., 2003). Th e consequences of poorly managed acute and chronic pain are potentially quite signifi cant. Unrelieved pain is associated with medical (medica l complications, longer hospital stay, higher risk of infections), physiological (neuroplas ticity, sensitization, increased risk of chronic pain), psychological (distress), and socio economical (increased health care costs) consequences (Aasvang and Kehlet, 2007; Anand et a l., 1987; McCaff ery, 1977). Among children who report experiencing chronic pain for more t han 3 months, between one-half and two-thirds continue to report chronic pain 1 and 2 years later, respectively (Perquin et al., 2003). Th e mechanisms underlying the transition from acute to chronic pain are not fully understo od. It is likely that they involve a com- bination of biopsychosocial, behavioral, and phys iological com- ponents (Priest and Hoggart, 2002). Identifying risk factors for the develop ment of chronic pain can lead to preventive programs including treatment before the pain be gins, or before it has become chronic. Th is would help prevent the processes that are invo lved in the development and maintenance of chronic pain. Primary, secondary, and tertiary prevention of pediatric pain Prevention of pediatric pain not only focuses on eff ectively man- aging and averting acute pain due to iatrogenic cause s (e.g. from medical and surgical origins), but also on ensuring that acute pain In this chapter, we focus on the biological and psychologi- cal factors associated with the development of pediatric chronic SECTION 1 introduction 40 PREVENTION ACUTE PAIN PREVENTION CHRONIC PAIN PRIMARY PREVENTION: Preventing acute pain from iatrogenic origin from occurring PRIMARY PREVENTION: Preventing acute pain from becoming chronic SECONDARY PREVENTION: Preventing early chronic pain from persisting or worsening TERTIARY PREVENTION: Treatment and management of chronic pain and disability Figure 5.1 Primary, secondary, and tertiary prevention of pediatric pain. ACUTE PAIN CHRONIC PAIN does not become chronic and disabling. It is essential to develop intervention strategies t hat target these various forms of preven- tion, namely primary, secondary, and tertiary (se e Figure 5.1 ). 1991) is widely used to evaluate functional disability in children with chronic pain; howev er, the source of disability is not speci- fi ed in the FDI. Th is lack of specifi city may impede eff orts aimed at reducing pain-related disability or at validating theoretical mod els of pediatric pain-related disability. Other pain-specifi c and oft en population-specif i c scales, such as the Child Activity Limitations Interview (CALI; Palermo et al., 2004), the PROMIS Pediatric Pain Interference Scale (Varni et al., 2010), the Pediatric Migraine D isability Assessment (PedMIDAS; Hershey et al., 2001) can be used by clinicians and researc hers to assess the extent to which the pain per se contributed to the child \200\231s disab ility. Future research directions include the evaluation of theoretical models of pain-re- lated disability using these scales as well as examination of the con- vergent validity of global functional and pain-related disabilities. Preventing acute pain of iatrogenic origin Preventing acute pain generally refers to the an ticipation and avoidance of pain onset. Complete prevention of acute pain is not desirable; children learn coping skills and safety behaviors from experiencing minor cuts, bruises, s crapes, etc. Many eff orts have been made, through programs such as Safe Kids USA and Safe Kids Canada to prevent serious injuries and traumas and indirectly prevent children from ex periencing pain. While these programs are examples of primary prevention, they will not be reviewed here given the lack of a pain-specifi c focus. Rather, the focus will be on acute pain from invasive medical and surgical procedures, as it can have long-lasting consequence s including preprocedural anxiety, hyperalgesia, avoidance of health care, development of c hronic pain, and disability. Prevention of acute pain of iatrogenic origin relies on neutra lizing the risk factors associated with the onset of acute pain. Interventions that decreas e the risk of developing acute pain are amongst the most cost-eff ective in managing pain. Th eoretical models and theories Prevention of chronic pediatric pain relies on the identif i cation and appropriate modifi cation of empirically validated causal risk, protective, an d prognostic factors. A critical examination of cur- rent theoretical models may help in th e search for factors that can ultimately be used in preventing pediatric chronic pain (see also Pillai Riddell et al., Chapter 9, this volume). Preventing the development and maintenance of chronic pain Primary prevention refers to the early identifi cation of acute pain and management strategies to ensure the pain does not become chronic. Identifi cation of risk factors for chronic pain and interven- tion strateg ies aimed at modifying these factors when the pain is acute are strategies associated with primary prevention of chronic pain. Th e causal risk and protective factors, and hence, the mecha- nisms underlying the transit ion from acute to chronic pain and the maintenance of chronic pain likely involve a combina tion of various components (e.g. biological, psychological, sociocultural, genetic). Althou gh some researchers have proposed theoretical models of the development and persistence of pediatric pain (Palermo and Chambers, 2005) most have been developed either for adult pain populations or are pediatric models not specifi c to chronic pain. Th e dominant models are summarized as follows. Secondary prevention consists of preventing early chronic pain states from worsening or per sisting. Identifi cation and modifi ca- tion of prognostic factors with the aim of reducing or eliminating the chronic pain experience are examples of secondary prevention strategies . Th e operant conditioning model (Fordyce et al., 1968) posits that pain behaviors are infl uenced by a system of punishment, rein- forcement, and extinction. It also stipulates that pain behaviors may become independent of physiological and sensory elements and occur in re sponse to external reinforcement contingencies. Th e fear-avoidance models of pain (Asmunds on et al., 2004; Leeuw et al., 2007; Vlaeyen et al., 1995) illustrate the relationships amo ng pain- related catastrophic thinking, pain-related fear/anxiety, and pain perception. In the absence of pain-related fear, symptoms of pain are confronted, leading to recovery. Alt ernatively, when pain symp- toms are interpreted catastrophically, pain-related fear and an xiety Tertiary prevention refers to the reduction of pain-related disa- bility and impairment, as well as the improvement of quality of life. Tertiary prevention also focuses on identifyin g and removing bar- riers to treatment, facilitating treatment adherence, and improving ada ptive daily functioning. Until recently, the lack of a pediatric pain-related disability or pain interference tool h as hindered research on tertiary preven- tion. Th e Functional Disability Index (FDI; Walke r and Green, CHAPTER 5 prevention of the development and maintenance 41 reactions ensue, followed by avoidance behaviors and hypervigi- lance of somatic symptoms, in particular pain, followed by disuse, disability, and depression, which in turn feed back into the pain experience to fuel pain-related fears in a never-ending cycle. Th e recently developed pediatric fear-avoidance model of chronic pain (Asmundson et al., 2012) adds to the adult fear-avoidance model child/adolescent factors and parental variables that contrib ute to the development and maintenance of chronic pain. More specifi - cally, parental pain management behaviors (e.g. protectiveness, solicitousness) and child psychological respons es (e.g. catastro- phizing, acceptance) will interact and infl uence child psychologi- cal response and escape/avoidance behaviors (Asmundson et al., 2012). Th e diathesis-stress mod el of chronic pain and disability (Turk, 2002) explains the progression from acute pain fol lowing an injury/ trauma to chronic disabling pain in adults. Th e model stresses sev- eral constructs as major predictors of the development of chronic pain and the maintenance of d isability: (1) a predisposing factor: anxiety sensitivity; (2) cognitive processes: fear of further pain and harm, catastrophizing cognitions, and low self-effi cacy; and (3) operant processes. A modifi cation of the model to include symp- toms of post-traumatic stress dis order has received empirical sup- port in patients before (Martin et al., 2010) and aft er (Kleiman et al., 2011) surgery. Taken together, these results suggest the models are relevant to the pediatric population b ut important components remain to be tested in children and adolescents. Research has been slow to identify factors responsible for the development and maintenance of chronic pain and disability in children. Th is is in part because of: (1) the relative a bsence of theo- retical models conceptualized (or adapted) specifi cally for paedi- atric p opulations, (2) the heterogeneity of pain outcomes assessed by current adult theoretical pa in models, and (3) the absence of empirically validated questionnaires to measure construct s relevant to specifi c models. While it is clear that factors identifi ed in the fol- lowi ng section are associated with pediatric pain, they have been mainly examined in isolation from one another. Remediating this lack of an integrative framework might be a necessary su bsequent step through which underlying mechanisms can be identifi ed (Huguet et al., 2011). Importantly, as mentioned earlier, the primary outcome of inter- est diff ers from one mode l to the other (e.g. pain behaviors, pain experience, chronic pain, and disability). Predic tor variables in one study are commonly used as outcome measures in other studies and vise versa, refl ecting the complexity of the problem and the variety in hypothesized mechanisms (Katz, 2012). As such, these diff erences must be taken into account when creating integra tive models of chronic pain. One of the challenges is to develop suf- fi ciently broad mode ls of the factors hypothesized to be associated with chronic pain outcomes. Recent advances in the quality of clin- ical research are due in large part to recommendations regarding a ssessment of core domains of functioning (Turk et al., 2003); the issue of the most appropr iate measure with a given domain how- ever, remains to be determined (Turk et al., 2008). C ore outcome domains that have been recommended to be included in pediatric clinical trials include pain, physical functioning/physical recov- ery, emotional functioning, role functio ning, patients \200\231 satisfaction with treatment, symptoms and adverse events, sleep, an d economic factors (McGrath et al., 2008). Th is type of integrative research is essential to the elaboration of testable hypotheses about underlying mechanisms of pediatric chronic pain and disability, leading to the elaboration of prevention strategies. Th e integrative model of parent and family factors in pediatric chronic pain and associate d disability (Palermo and Chambers, 2005) emphasizes the importance of parents and family t o under- stand the child \200\231s pain experience and specifi cally suggests three interre lated levels of factors that infl uence pain and disability: (1) individual factors (e.g. p arental behaviors), (2) parent \200\223 child interactions, and (3) family-related variable s (e.g. familial environment). Th e biopsychosocial model of pain (Engel 1977; Gatchel et al., 2007; Turk, 1996) posits th at \200\230pain \200\231 is a subjective idiosyncratic experience that includes biological (e.g. autonomic, endocrine, and immune systems, genetic predispositions), psychological (e .g. fear, anxiety, previous pain experiences), and social (e.g. cultural and familial) aspe cts. Th e perceived self-effi cacy model of chronic pain (Bursch et al., 2006; Vuorimaa et al., 2008) states that beliefs about one \200\231s ability to cope with pain and to maintai n everyday life activi- ties despite pain will impact one \200\231s regards towards pain co ntrol, pain coping, and daily functioning, which in turn regulates pain and associated disa bility. Th e modeling/social learning theory (Bandura, 1986; Craig and Prkachin, 1978) emph asizes the important role of modeling; that is, the capacity to learn a wide range of behav iors, such as complex pain behavior patterns, through observation of pain behaviors of othe rs. Th e potency of modeling as a method of learning can be enhanced by the consequences (r einforcement or punishment) of the modeled behavior, the consequences that meet the imitati ve behavior adopted from the model, the expect- ancies of one \200\231s abilities to execut e the modeled behavior, and the outcome expectancies of future consequences. Last, the atta chment theory (Bowlby, 1973) when applied to pain suggests that pain serves as a signal of threat and consequently activates a sequence of attach- ment behaviors, which in turn will infl uence the pain experience. Common correlates, predictors, markers, and prognostic factors of chronic pain and disabili ty Th e literature has focused mostly on fi nding correlates of chronic pediatric pain usin g cross-sectional studies and only more recently on fi nding risk/protective and prognostic factors associated with the onset and course of pediatric chronic pain. Th e factors that have been more commonly explored through a cross-sectional or longitudinal design are: (1) demographic characteristics (i.e. gender and age; Egger et al., 1998; Sjolie, 2002; Vikat e t al., 2000), (2) health status (e.g. Vikat et al., 2000), (3) anthropometric characteristi cs (Kovacs et al., 2003; Sjolie, 2002), (4) physical conditions (Kovacs et al., 2003), (5) mechanical characteristics (Bejia et al., 2005; Jones et al., 2003), (6) sleep problems and physical activity (Laurell et al., 2005; Vikat et al., 2000), and (8) smoking (Kovacs et a l., 2003). In addition, the following factors have been studied as poten- tial correlates, predictors, markers or prognostic factors of paedi- atric pain-related disability: (1) demographic cha racteristics (i.e. age and sex; Konijnenberg et al., 2005; Logan and Scharff , 2005); Speci \201 city of pain models Most models described have not been evaluated in children a lthough there is support for various components (see Table 5.1 ). SECTION 1 introduction 42 Table 5.1 Empirical support for pain and pain-related disability models in pediatric popula tions Outcome Predictors Person-centered models Systemic models Operant Diathesis Fear-avoidance Biopsychosocial Perceived self- e \203 cacy Social learning Attachment theory Chronic pain Anxiety sensitivity (Tsao et al., 2009) Pain-related fear and pain anxiety (Simons et al., 2011) Pain catastrophizing (Crombez et al., 2003; Vervoort et al., 2006) Self-e \203 cacy (Bursch et al., 2006; Vuorimaa et al., 2008) Biological (e.g. age, gender, genetic factors) (El-Metwally et al., 2008; Hechler et al., 2 010; Martin et al., 2007b) Psychological (e.g. coping, distress) (Gauntlett-Gilbert and Ecc leston, 2007) Social (e.g. family, parental response) (Logan and Schar \200 , 2005) Perceived self- e \203 cacy (Bursch et al., 2006; Vuorimaa et al., 2008) Punishment reinforcement expectancies of modeling (Allen and Shriver, 1998; Minuchin et al. , 1975) Attachment style Disability/ disuse Pain catastrophizing (Crombez et al., 2003; Lynch et al., 2006; Vervoort et al., 2006) Pain -related fear and anxiety (Martin et al., 2007a) Pain-related fear and avoidance (Wilson et al., 2011) Perceived self- e \203 cacy (Bursch et al. 2006) Attachment style (Walsh et al., 2008) Pain behaviors Punishment reinforcement (Allen and Shriver, 1998; Minuchin et al., 1975) Prevention strategies for pediatric pain Prevention strategies can be classifi ed into the following three domains: physical, psychosocial, and pharmacological. A com- bination of mo re than one approach will be optimal in prevent- ing the development and/or maintenance of pain in children. As highlighted in the theoretical models previously described, sensory, c ognitive, and aff ective factors are thought to interact to predict pediatric pain and disa bility. It follows, then, that pain preven- tion will also involve a multidisciplinary appr oach which will vary according to the level of intervention. (2) general health status (Claar et al., 1999; Konijnenberg et al., 2005); (3) psychologica l characteristics such as depression, vulnerability, or psychological distress (Logan et al ., 2006; Vervoort et al., 2006); (4) pain coping responses (Kashikar-Zuck et al., 2001; Saw yer et al., 2005); (5) catastrophic thinking (Kashikar-Zuck et al., 2001; Vervoort et al., 2006); (6) environmental contingencies to pain behaviors (Craig and Pillai Riddell, 2003; V an Slyke and Walker, 2006); and (7) parental or family characteristics including parental p ain, parental distress, parental stress (Logan and Scharff , 2005). Recently, pain unpleasa ntness has been found to be associated with the transition from acute to chronic pain while anxiety sensitivity has been associated with the maintenance of chronic pain aft er sur- g ery (Pag et al., 2013). Whereas clinical pain management relies increasingly on multi- modal approaches (e.g. pain management in neonates; Allegaert, 2009; Parry, 2011), research typically focuses on unidim ensional aspects of pain prevention and management. A good example of this disconnect betwe en clinical practice and research can be found in the literature on recurrent abdominal pai n (RAP). Th ree Cochrane reviews focus on the tertiary prevention of RAP: one focuses on di e- tary management (Huertas-Ceballos et al., 2009), a second focuses on pharmacological int erventions (Huertas-Ceballos et al., 2008a), and the third examines psychosocial interventi ons (Huertas- Ceballos et al., 2008b). Individually, these reviews provide important Systematic reviews and meta-analyzes will make it possible to identify the most important e vidence-based factors that contribute to the development and course of pediatric pain and d etermine the specifi c and common factors associated with particular pain conditions (Hugue t et al., 2011). At the moment, the most common factors that are considered to be correlate s, predictors, markers or prognostic factors of pediatric pain are highlighted in Table 5.2 , based on published reviews. Th e majority of these reviews, how- ever, are non-systemati c. CHAPTER 5 prevention of the development and maintenance 43 Table 5.2 Reviews of predictors of pediatric pain (systematic and non-systematic) Pain condition Authors Outcome Findings (Gieteling et al., 2011) a Recurrent abdominal pain Persistence of RAP Predictors: prognostic factors, markers High levels of negative life events High levels of functional gastrointestinal complaints i n family Illness perception Female sex Behavioral disturbances Psychological disorders Seve re abdominal pain. Young age Low educational level Depressive/anxiety disorders Self-percei ved academic competence Long duration of abdominal pain History of two or more surgeries Pr esence of other associated symptoms (nausea, vomiting, headaches) High levels of functional disability Low socioeconomic status Attitude towards health care Non-signi \201 cant predictors, prognostic factors, markers: Unclear/still unknown: (Schar \200 , 1997) RAP Correlates, predictors, prognostic factors, markers: Underlying physiological predisposition Dietary in \202 uences Anxiety Recent stressful ev ents and coping abilities Family issues (Schulte et al., 2010) Development of RAP Predictors, prognostic factors, markers: Abdominal in \202 ammation processes Familiar genetic vulnerability to gastrointestinal sy mptoms and psychopathology Temperament Life events and stressors Psychopathological comorbi dity Maladaptation to RAP Predictors, prognostic factors, markers: Maladaptive pain processing Maladaptive pain communication in the family Maladaptive coping style Psychopathological comorbidity (Chogle and Saps, 2009) RAP Correlates, predictors, prognostic factors, markers: Stress, school-related stress Parent-related factors psychological factors Family demograph ics Seasonal variations Infectious agents Altered intestinal \202 ora Antibiotics Diet Recurrent pediatric headache (Martin and Smith, 1995) Recurrent pediatric headache Correlates, predictors, prognostic factors, markers: Depressive and symptoms Stress Multiple somatic symptoms Exposure to pain models Internaliz ing behaviors (+ externalizing behaviors for boys) (Continued) SECTION 1 introduction 44 Table 5.2 (Continued) Pain condition Authors Outcome Findings Musculoskeletal pain (Malleson et al., 2001) Predictors, prognostic factors, markers: Intrinsic factors: Low pain thresholds Female gender Hypermobility Poor perceived control o ver pain and maladaptive pain coping strategies Di \203 cult temperament Extrinsic factors : Previous pain experiences Social deprivation Physical or sexual abuse Parenting modeling of pain behaviors Sleep disturbance Exercise Development of musculoskeletal pain/ \201 bromyalgia and disability (Prins et al., 2008) a Development of the upper quadrant musculoskeletal pain Predictors, prognostic factors, markers: Static sitting posture Depression Stress Psychosomatic symptoms Gender Age a Systematic reviews. prevention and treatment approaches to childhood RAP, but they do not provide a comprehensi ve, multidisciplinary approach to the treatment of RAP nor do they provide insight into the eff ectiveness of combining, or the optimal combination of, various approaches. Methodolog ical challenges and realistic constraints and costs asso- ciated with conducting multidisci plinary, multiple group studies may, in part, explain this lack of integrative research. In vestigating the effi cacy of separate interventions is a good fi rst step in design- ing pr evention and treatment programs. But it is important to keep in mind that the outcome of su ch research results in isolated islands of knowledge and a lack of understanding of the opt imal multidisciplinary treatment combination that would be most eff ec- tive. Th e next ste p would be to conduct outcome research combin- ing multiple interventions consisting of tho se that have been shown to be the most eff ective. provide a better integration of research into clinical practice and focused specifi cally o n postoperative pain control, pain assess- ment, needle-related pain, and encouraging paren tal involve- ment in children \200\231s pain management. Th is type of model is essential t o knowledge translation and the implementation of systematic programs aimed at preventing a nd reducing acute pain in hospital. Two important areas targeted by this model are procedural pain and postoperative pain. Beca use the timing and nature of these procedures are known in advance, it is possible to condu ct lon- gitudinal studies beginning prior to the procedures in order to identify risk and p rotective factors associated with the acute pain experience. Systematic reviews of the literature on procedural pain have supported development of clini cal practices guidelines that outline effective pharmacological and non-pharmacological int erventions (including contextual, behavioral and cognitive strategies) to reduce procedural pain (e.g. Taddio et al., 2010) (see Table 5.3 ). Th e non-modifi able factors identifi ed earlier (e.g. age, sex) can help in identifying ch ildren at higher risk of developing pain and engage them in early prevention treatments. Mo st of the prognos- tic factors, predictors, and risk factors, however, are modifi able and intervention strategies should focus on minimizing the risk of developing pain or maintaini ng pain and pain-related disability associated with these factors. Research has also focused on reducing acute postoperative pain. One randomized controlled t rial on the effectiveness of behavioral interventions on post-operative pain in children sh owed that behavioral preparation reduces anxiety before surgery and during induction of ane sthesia, and leads to lower frequency of emergence delirium, lower consumption of anal- ges ic in the recovery room, and shorter stay in the recovery room (Kain et al., 2007). Guided imagery has also been found to reduce levels of pain and anxiety hours, but not 1 day after surgery when used 1 week and a few hours before surgery (Huth et al., 2004). Primary prevention of acute pain of iatrogenic origin Signifi cant eff orts have been deplo yed to prevent or reduce pain during hospitalization. A forerunner of this type of preventi on was the implementation of the \200\230ouchless place model \200\231 in the 1990s (Schec hter, 2008). Th e goals of this program were to CHAPTER 5 prevention of the development and maintenance 45 Table 5.3 Evidence-based interventions to reduce procedural-related pain (i.e. immunization and injection pain) in infants, children, and adolescents Systematic reviews evaluating the e \200 ect of these interventions Non-pharmacological management Infants Breastfeeding Kangaroo care (skin-to-skin contract) A sweet-testing solution Swaddling/faci litated tucking Rocking/holding Sucking-related interventions (Pillai Riddell et al., 2011; Stevens et al., 2010) (Cepeda et al., 2006; Chambers et al., 2009; Uman et al., 2006) Children and adolescents Psychological interventions: \227\206 Distraction (e.g. music, cartoon movies) \227\206 R elaxation breathing \227\206 Information/preparation \227\206 Combined cognitive-behavior al interventions Physical interventions/injection technique: \227\206 Injecting the least painful brand during vaccination \227\206 Having the child sit up \227\206 Stroking the s kin or applying pressure close to the injection site before and during injection; \227\206 Injecting the most painful vaccine last when 2 vaccines are being administered sequentially during a single o \203 ce visit; \227\206 Performing a rapid intramuscular injection without aspiration. Pharmacological interventions