Safe opioid analgesic therapy dose scheduling for burn patients: a cross-sectional study


Danielle de Mendonça HenriqueI; Lolita Dopico da SilvaII; Flavia Giron CameriniIII; Karla Biancha Silva AndradeIV; Sandra Regina Maciqueira PereiraV; Cintia Silva FassarellaVI

INurse. PhD in nursing. Adjunct Professor, Faculty of Nursing, State University of Rio de Janeiro. RJ, Brazil. E-mail: danimendh@gmail.com
IINurse. PhD in nursing. Adjunct Professor, Faculty of Nursing, State University of Rio de Janeiro. RJ, Brazil. E-mail: lolita.dopico@gmail.com
IIINurse. PhD in nursing. Adjunct Professor, Faculty of Nursing, State University of Rio de Janeiro. Brazil. E-mail: fcamerini@gmail.com
IVNurse. PhD in nursing. Coordinator of the Intensive Care Center of the National Cancer Institute. Rio de Janeiro, RJ, Brazil. E-mail: k.biancha@ig.com.br
VNurse. PhD in nursing. Adjunct Professor, Faculty of Nursing, State University of Rio de Janeiro. RJ, Brazil. E-mail: sandregina@gmail.com
VINurse. PhD in nursing. Adjunct Professor, Faculty of Nursing, State University of Rio de Janeiro. RJ, Brazil. E-mail: cintiafassarella@gmail.com

DOI: http://dx.doi.org/10.12957/reuerj.2017.28082




Objectives: to describe opioid therapy in analgesia for burn patients, and to identify drug interactions in the scheduling process, thus contributing to prevention of respiratory depression. Methods: this retrospective study examined 272 medical records of burn patients hospitalized between 2011 and 2013. Naloxone administration, blood pressure lower than 110/60mmHg, orotracheal intubation, pulse oximetry less than 90%, respiratory rate less than 10 bpm, need for oxygen, and abrupt opioid discontinuation. Results: analgesia was predominantly with the opioids: tramadol (45.49%) and methadone (18.45%). Predominant administration times were 10pm and 6pm. There was potential for drug interactions in 66.6% of the cases, while 88.8% of the drug pairs studied can cause severe harm. Conclusion: when scheduling the prescribed medication, nurses should be aware that inappropriate opioid dose scheduling may lead to drug interaction, potentiating pharmacological effects, with the risk of loss of consciousness and respiratory depression.

Keywords: Critical care; analgesia; respiratory insufficiency; patient safety.




Burns are traumatic wounds caused in most cases by thermal, chemical, electrical or radioactive agents. According to data from the World Health Organization1 (WHO), about 300,000 people die each year from burns worldwide, and millions of people suffer from disfigurement and dysfunction caused by scars, psychological trauma and significant loss of economic productivity. According to the Brazilian Society of Burns (BSB), one million cases occur each year in Brazil, of which 200 thousand are treated in emergency services and 40 thousand require hospitalization 2.

Opioid analgesics are the most commonly used for the treatment of burn pain. Factors that justify the choice for this drug class include potent analgesia; pharmacokinetic profile (ease of absorption, distribution and excretion); variety of administration routes; and also the promotion of a certain degree of sedation, depending on the dose administered, which may be particularly advantageous during burn-care procedures3.

Opioids are considered to be potentially dangerous drugs (PDD), as they have the potential to cause harm to patients, even when used as intended. The Institute for Safe Drug Practices (ISDP) reports that although errors in the use of these drugs are not common, the impact on patients when they occur can be severe and may even lead to death4.

The wide spectrum of opioids available for clinical use confers flexibility of dosage, since its pharmacological presentation allows the administration by different routes (oral, enteral, rectal, subcutaneous, intravenous, epidural, transdermal and by inhalation), offering different possibilities for the treatment of pain in burned patients. However, this variety also suggests a higher risk when it comes to drug safety4.

Among the effects associated with the use of opioids, the most serious is respiratory depression (RD), which is considered an adverse event and usually preceded by excessive sedation. Given the severity of this event, preventive measures have been discussed in different patient safety forums 5.

In high complexity units such as the Treatment Center for Burn Patients (TCBP), nurses are responsible for the release, preparation and administration of opioids by different routes. Thus, it is the responsibility of nurses to evaluate the medications based on pharmacological knowledge, evaluating the possibility of drug interactions that may potentiate the effect of opioids and favor the occurrence of RD. After administering an opioid, nurses should not only monitor the effects of the drug on the patients, but also the appearance of possible events that may predict RD.

All these aspects involving the use of opioids were the basis of this research whose objectives were to describe the opioid therapy used for analgesia in burn patients and identify drug interactions, based on errors in the process of hospitalization, contributing to the prevention of RD.



Burns are classified according to depth of the burn and the body surface affected. Burn pain is related to these factors; the deepest are classified as third degree burns and may involve destruction of the afferent nerve, theoretically reducing the pain in the site, although in clinical practice, this is not always a reliable indicator6.

It is of the utmost importance that the burn victims be constantly evaluated for pain in order to guide the analgesic conduct and the response to medication. Features such as site of the pain, factors of improvement or worsening, type and intensity of pain are also essential to management. Opioids are analgesic drugs commonly used for treatment of moderate to highly intense pain3.

Analgesia with opioid drugs should be individualized, considering the clinical conditions of the patients, the intensity of pain, the efficacy of the response to analgesia after careful administration of the drug, and the presence of undesirable effects. Thus, knowledge on pharmacokinetics is fundamental, since the absorption, distribution, metabolism, and excretion of opioids can be altered7.

The combined use of medications for the purpose of additive or potentiated analgesia with lower individual doses and reduction of undesirable effects is a common practice in the treatment of pain, especially burn pain. This practice, although widely used, may favor drug interactions and alter the pharmacokinetics of opioids8.

In order to avoid drug interactions, nurses should be able to relate pharmacodynamic and pharmacokinetic characteristics of the drugs to the possibility of adverse events resulting from the use of opioids. It is necessary to recognize as early as possible the main signs to be monitored after administration of opioids, besides identifying those patients at higher risk for RD9.

Safe use of opioids, associated with nursing actions, involves the medication process, patient monitoring and recognition of predisposing factors for RD. Nurses have the responsibility for the implementation of barriers to prevent RD in burned patients using opioid drugs9.



A retrospective study was carried out in the first semester of 2014. A total of 272 medical records of burned patients hospitalized between 2011 and 2013 were analyzed at the Treatment Center for Burned patients (TCBP) of a federal public hospital in the municipality of Rio de Janeiro. Complete medical records were selected, with discharge or death as outcome, of patients with a minimum length of stay of 48 hours, aged over 18 years, who used opioids through different routes of administration, monitored with pulse oximetry, and without a ventilatory prosthesis.

RD episodes were screened in the medical records that met the selection criteria, , which confirmed at least two indicators, among them: administration of Naloxone, blood pressure less than 110/60mmHg, orotracheal intubation, pulse oximetry less than 90%, respiratory rate less than 10 breathing cycles per minute (bcpm), need for oxygen supply, and abrupt opioid interruption.

In order to achieve the objectives proposed by the research, the following variables were analyzed: drugs used in the analgesia of the burned patients, pattern of drug release, and the occurrence of drug interaction. The identification and classification of the drug interaction was performed by Micromedex software10.

The medical records that met the selection criteria were divided into two groups. The group G1 corresponded to patients who presented RD and the group G2 to patients without RD. The variables were submitted to descriptive and inferential statistics, and a 95% confidence interval was calculated for the calculation of p-values using the Fisher's Exact Test. Association measures such as Odds Ratio (OR) and Relative Risk (RR) were also used.

The study project was submitted to institutional approval by means of a letter authorizing the research, and by the Research Ethics Committee (REC) of the institution, obtaining approval by the consubstantiated Opinion of REC - nº 453.911/2013, on November 11, 2013.



A total of 272 medical records of burned patients hospitalized between 2011 and 2013 were analyzed, but only 42 medical records met the selection criteria of the study, and from these, 12 (28.58%) presented 24 episodes of RD. In the 42 medical records analyzed, 255 doses of prescribed analgesics were identified, and all drugs were classified according to the Anatomical Therapeutic Chemical (ATC) classification system.

Among the analyzed doses, opioid analgesics predominated in the groups with and without RD. Among opioids, the most noteworthy were tramadol, 116 (45.49%), and methadone, 47 (18.43%). Among the available benzodiazepines, only diazepam (n = 27) was used and its ratio was similar between the groups with and without RD. Among the tricyclic antidepressants, imipramine predominated; and among anticonvulsants, gabapentin was more frequently used by patients who did not present RD.

In order to aid the analysis of the management of the analgesic therapy, it was necessary to identify how nurses organize the timing of this therapy in the release of the prescribed drugs to the burned patients.

It was observed that in both groups, with and without RD, there was a predominance of release at 22h and 06h, but inversely. In the group of patients with RD, the predominant time, with the highest concentration of medications, was 22h.

The concentration of release at the abovementioned hours has the consequence of potential drug interaction (PDI). Thus, the association between exposure to PDI and occurrence of RD was the tested.

Patients who were exposed to PDI due to the mode of medication release are listed in the Figure 1, with the respective variables of interest for the research.

Legend: Respiratory depression (RD); Burn Treatment Center (BTC); Burned Body Surface (BBS); Potential Drug Interaction (PDI).
Note: (*) Death - Y = yes and N = no.
: Overview of patients with RD in whose prescriptions were identified PMIs. Rio de Janeiro, 2014.

The Figure 1 presents an overview of the patients who had RD according to the burned body surface (BBS), occurrence of predominant risk factors for RD, PDI schedule, RD schedules, drug pairs involved in the PDI, and the occurrence or not of death.

Although no significant difference (p-value = 0.1379) was found between the two groups, the OR and RR were calculated and showed a positive association. There was a three-fold greater chance of RD in patients with PDI and a 2.5-fold increased risk of RD in these patients. See Table 1.

TABLE 1: Distribution of the occurrence of PDI in patients with and without respiratory depression. Rio de Janeiro, 2014.

Legend: respiratory depression (RD); Potential drug interaction
Note: Fisher's exact test (CI: 95%).

The drug pairs involved in PDI, their classification as to severity and the level of evidence of these drug interactions, in the prescriptions released in the TCBP, in patients with and without RD, are described in Figure 2.

Legend: respiratory depression (RD); Potential Drug Interaction (PDI).
Source: Micromedex6.
FIGURE 2: Pairs of drugs involved in Potential Drug Interactions. Rio de Janeiro, 2014.

It is observed that in the pairs of drugs studied, the number of PDIs (21) was higher in the 12 patients with RD, whereas in the 30 patients without RD, 15 PDIs occurred, as detailed in Figure 2.

In the studied TCBP, the pairs of prevailing drugs with PDI in patients with RD were methadone with diazepam (n = 5) followed by tramadol with fentanyl (n = 4), methadone with imipramine and methadone with tramadol (3). See Figure 2.

In the group without RD, PDIs occurred in the cases of administration of methadone with tramadol (n = 8), tramadol with fentanyl (4), and methadone with diazepam (3). The most prescribed drugs also appear among the prevalent involved in PDI, as it is the case of tramadol, methadone and diazepam.

Regarding the severity of the PDIs, the data show that, in TCBP studied, there was a predominance of associations that induce serious damage. Regarding the documentation of PDIs, most are good; only the association of tramadol with imipramine was weak. See Figure 2.

The study indicates that patients with a median burned body surface (BBS) of 50%, and of age 47.5% have severe RD. The prognosis of younger patients was better, eight out of12 patients with RD died; among the four survivors, the younger ones predominated, with a mean age of 32.5 years, and the oldest of the survivors had the lowest BBS. See Figure 1.

Another factor that should be considered is the occurrence of risk factors for RD due to opioids. Renal failure was identified in 11 (91.6%) of the RD patients, cardiovascular diseases in 6 (50%) and all had hypoalbuminemia, which is characterized as a typical condition of burned patients and favors the possibility of RD.

We observed that 10 (83.33%) individuals with RD presented PDI, with a predominance of the 22h and 06h schedules. The drugs of higher interaction were methadone with diazepam and tramadol and fentanyl, which were administered through oral, intravenous and transdermal routes. The PDI schedules were close to the registered RD schedules.

The drug with the highest number of prescribed doses was tramadol. This drug is, therefore, more likely to cause PDI. On the other hand, despite having a lower number of prescribed doses, morphine offers a greater risk of RD.

Proportionally, it was observed that from the 38 doses of tramadol prescribed in patients with RD, PDI was identified in eight cases. In turn, morphine was used in only one patient who had RD, and all the four administered doses had PDI.



In this research it was evidenced that the analgesic therapy of burn patients is performed through different drug classes, with opioids as the basis of this treatment; still, tramadol and methadone were the drugs most used in the studied population.

Analgesia with opioids should be individualized. The clinical conditions and intensity of pain of the patient, the effective response to analgesia after careful administration of the drug, and the possible presence of undesirable effects should be considered. Thus, knowledge on pharmacokinetics is fundamental, because the absorption, distribution, metabolism and excretion of opioids can be altered11.

Hypermetabolism in burned patients, which occurs in the first 24 to 48 hours after the burn, causes an increase in extracellular fluid volume, causing possible changes in glomerular filtration. These characteristics may alter the pharmacokinetic and pharmacodynamic response of opioids, potentiating or reducing their effects on burned patients12,13.

The combined use of drugs for the purpose of obtaining additive or potentiated analgesia with lower individual doses and reduction of undesirable effects is a common practice in the treatment of pain, especially burn pain14. This explains the use of different drug classes in this study.

Besides opioids, other medications such as gabapentin are used. The latter is an anticonvulsant, but is currently also prescribed for the management of neuropathic pain. There is evidence that this drug assists in the reduction of pruritus in the epithelization phase of burns15,16.

Benzodiazepines have no analgesic properties and should not be used as such, but are useful and effective in reducing the perception of pain in anxious patients. Antidepressants, such as amitriptyline and imipramine, in low doses, have a comfirmed role in the management of neuropathic pain 15-17. Nurses need to have specific pharmacological knowledge to contribute to the prevention of adverse events of opioids18.

In this study, tramadol and methadone were the most evident in the treatment of burned patients. Nurses should be able to administer such drugs, identify their pharmacological properties and expected therapeutic effects, basing their conducts on this knowledge18.

It is understood that when nurses manage the drug therapy of burned patients, they should monitor them during and after drug administration and recognize early side effects of each drug in order to evaluate intervention measures.

Regarding the profile of the release and PDI in the pharmacological therapy in burn patients, 66.66% of drug interactions in this study were identified as resulting from errors in drug release. At the moment of scheduling the administration of opioids, nurses should be aware of the pharmacodynamic characteristics of the drug, ensuring the efficacy of the analgesia and avoiding PDIs.

The pharmacokinetics of opioids may be altered by drug interactions, particularly by hypnotic-sedatives, antipsychotics, and monoamine oxidase (MAO) inhibitors19,20.

According to the search conducted in Micromedex®10, drug interactions capable of causing RD were identified and they are considered serious. Drug interactions should be known by nurses, so that they can be avoided by delaying a prescription, contributing to the prevention of adverse events related to drug therapy21.

The times of administration of drugs in the night shift – 22h and 06h – predominated in both groups of patients, with and without RD. There were no doses released at odd hours. The hours of drug release depend on the organization of the service in the sector, since the bath of burned patients and dressings are performed in the morning.

The organization and execution of drug release in the studied site appear to be strongly adapted to the institutional routine, being an activity that seems to receive little attention. Although knowledge is fundamental to avoid PDIs that can harm patients, there is an organizational logic in which nursing professionals follow standardized schedules without taking into account the possibility of drug interactions22.

Safe and accurate release of medication is an important responsibility of nursing professionals, who still perform it manually in most hospitals, following a fixed schedule routine that rarely considers the characteristics of the prescribed medication and/or the clinical situation of the patient, and this is the reality of the field of this study. Through drug release, nurses organize the drug therapeutic plan established for the patients and, in most hospitals, the pattern of time intervals is closely associated with the routine of nursing care, of doctors, and of the pharmacy service23.

In intensive care units, such as the TCBP, the prescriptions contain increasingly complex combinations, making it very difficult to foresee PDIs, which are those in which there is a possibility of changing the effect of the drugs involved and may lead to undesirable results, increasing the incidence of adverse effects of therapy without concomitant therapeutic benefit23.

Although their results may be both positive (increase in effectiveness) and negative (decrease in effectiveness, toxicity or idiosyncrasy), PDIs are usually unplanned and undesirable in pharmacotherapy. Results have shown that complications related to medication use are the most common type of adverse event in hospital admissions (19% of patients), and that 2-3% of the hospitalized patients experience reactions specifically provoked by pharmacological interactions23.

In this study, the most prevalent drug pairs related with PDIs were methadone with diazepam, tramadol with fentanyl, methadone with imipramine, and methadone with tramadol. It is recommended that the preparation of the medications be carried out in a safe environment, and that this environment be the one in which nurses will release medication, so that the professional may be able to consult tables and protocols, simple and practical resources to inform about the more common PDIs with intravenous drugs22.

Diversifying the schedules may be a strategy to reduce PDIs. We suggest the use of odd hours for drug release. Although the literature does not specifically address how medication timings should be distributed 4-24, the need to alternate opioid schedules with drugs that potentiate their effects, such as benzodiazepines, for example, was evident in this study.

Perhaps the ideal to avoid a drug release that can provoke PDI is the computerized prescription that guides the drug release. Several softwares that were exclusively developed for the purpose of checking the possible interactions between drugs are already available in the market, but they are not always within the reach of the nursing team, in their work places. Furthermore, the use of computerized drug prescription systems, when coupled with specific databases and specific calculators, enable physicians to instantaneously receive useful warnings about drug interactions when they are prescribing the drugs, preventing a drug release schedule that could cause a drug interaction. However, this tool still has some obstacles to be overcome, because of its high costs and the need for a reasonable infrastructure and training of the health team, a fact that explains the slowness of its implementation in the hospital system23.

The occurrence of a severe PDI due to a routine of drug release should be considered by nurses a mistake to be prevented. Errors should serve as tools to promote the quality of the service provided, foster changes in institutional and professional culture, encourage non-punitive attitudes, enable corrections to the system's flaws, and ensure greater patient safety 24.



This study identified that the pharmacological treatment of burned patients involves different drug classes. Yet, the basis of the treatment are opioids, evidenced by the predominance of the number of doses of these analgesics in both groups with and without RD. Tramadol and methadone are the most commonly used opioids.

In this sense, it is necessary for nurses to acquire knowledge about the potential effect of opioid therapy on excessive sedation and RD, so as to be able to recognize adverse drug reactions such as early identification of the progression of sedation and the importance of making timely adjustments in the care plan.

We recommend that health institutions create and implement policies and procedures for continuous clinical monitoring of patients receiving opioid treatment.

Most medical records contained data that, after analysis, indicated the PDIs. Patients with PDI presented a three-fold greater chance of RD. Undue drug release may contribute to the occurrence of drug interaction, and this interaction, in turn, may potentiate the pharmacokinetic and pharmacodynamic effect of the drug and, in the cases of patients taking opioids, this may lead to a decrease in the level of consciousness and RD.

We hope that this study advance the Brazilian scientific production on the topic of drug safety, fostering new studies in this area, generating knowledge and data source for consultation of health professionals, because RD caused by the use of opioids is an extremely serious adverse event, which should be the focus of discussion of the entire multidisciplinary team, generating safe assistance processes.



1.World Health Organization. Burn prevention: success stories and lessons learned. Geneva: World Health Organization, 2011. [cited in Jul 05, 2016]. Available from: http://apps.who.int/iris/bitstream/10665/97938/1/9789241501187_eng.pdf

2.Takino MA, Valenciano PJ, Itakussu EY, Kakitsuka EE, Hoshimo AA, Trelha CS, et al. Epidemiological profile of children and adolescents victims of burns admitted to a burn treatment center. Rev Bras Burns. 2016; 15 (2): 74-9.

3.National Network for Burn Care. National Burn Care Referral Guidance. UK: NHS Specialised Services, 2012. [cited in 2017 Jan 17]. Available from: britishburnassociation.org/referral-guidance

4.Institute for Safe Medication Practices. Potentially hazardous drugs for hospital and outpatient use - updated lists 2015: ISMP; 2015. [cited January 17, 2017]. Available from: http://www.ismp-brasil.org/site/wp-content/uploads/2015/12/V4N3.pdf

5.Kraychete DC, Siqueira JT, Garcia JB. Recommendations for the use of opioids in Brazil: Part II. Use in children and the elderly. Rev Dor. 2014;15(1):65-9.

6.Richardson P, Mustard L. The management of pain in the burns unit. Burns. 2009; 35(1): 921-36.

7.Lemonica L. Pharmacological basis for the clinical use of opioids. Rev Hospital practice. 2008; 10 (56): 1229-35.

8.Bolgiani AN, Serra MCVF. Update on the local treatment of burns. Rev Bras Queimaduras. 2010; 9 (2): 38-44

9.Henrique DM, Silva LD. Respiratory depression as a complication of opioid use: grounding the nursing care. Evidentia. 2014; 11 (1): 47-8

10.Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. [cited in 2017 Jan 17]. Available from: http://www.micromedexsolutions.com

11.Cavalcanti VL, Barcelos LS, Cavalcanti RLS. Knowledge of nurses in the control of burn pain in burned patientS. Magazine presença. 2016; 2 (5): 25-41

12.Henrique DM, Silva LD, Pereira SEM. Characteristics of burned patients, opioid user, and factors contributing to respiratory depression. Enfermería Global. 2016; 15 (43): 112-25.

13.Trupkovic T, Kinn M, Kleinschmidt S. Analgesia and sedation in the intensive care of burn patients: results of a european survey. J Intensive Care Med. 2011; 26(6):397-407.

14.Lima LS, Correia VOS, Nascimento TKGO, Chaves BJP, Silva JRS, Alves JAB et al. Profile Of Burn Victims Attended By An Emergency Unit. 2017;10(10):1-9.

15.Richardson P, Mustard L. The management of pain in the burns unit. Burns. 2009; 35(1): 921-36.

16.The Joint Commission. Safe use of opioids in hospitals. Sentinel Event Alert, Issue; 2012. p.49. [cited in 2017 Jan 12]. Available from: http://www.jointcommission.org/assets/1/18/SEA_49_opioids_8_2_12_final.pdf

17.Castro RJA, Leal PC, Sakata RK. Pain treatment in burn patients. Rev Bras Anestesiol. 2013; 63 (1): 149-58.

18.Pinho FM, Amante LN, Salum NC, Silva R, Martins T. Guideline of actions in nursing care to adult burned patients. Rev Bras Queimaduras.2016; 15 (1): 13-23

19.Institute of Healthcare Improvement. Campaign of 5 million lives, preventing damage caused by high-risk drugs. 2008 [cited in Feb. 20, 2017]. Available from: http://www.ihi.org/IHI/Programs/Campaign/

20.Katzung BG. Farmacologia básica e clínica. 9ª ed. Rio de Janeiro: Guanabara Koogan; 2006.

21.Henrique D.M, Silva, L.D. Safe use of opioids in burned patients: grounding the nursing care. Rev Bras Burns. 2014; 13 (1): 6-10. [cited in Jan. 12, 2017]. Available from: http://www.rbqueimaduras.com.br/detalhe_artigo.asp?id=190

22.Camerini FG, Silva LD. Patient safety: analysis of the preparation of intravenous medication in a sentinel hospital. Text Context Enferm. 2011; 20 (1): 41-9.

23.Silva LD, Matos GC, Barreto BG, Albuquerque DC. Drug release by nurses in sentinel hospital prescriptions. Texto contexto enferm. 2013; 22 (3): 722-30

24.Lima CSP, Barbosa SFF. Occurrence of adverse events as indicators of quality of care in an intensive care unit. Rev Enferm UERJ.2015; 23 (2): 222-8.