Fixed Dose of Intravenous Hydromorphone in the Treatment of Acute Pain

Acute Pain Clinical Trial

Official title:

Safety and Speed of Onset of a Fixed Dose of Intravenous Hydromorphone in the Treatment of Adult Patients Presenting to the Emergency Department With Acute Severe Pain

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01006850
• Other study ID #: MMC05-11-307
• Status: Completed
• Phase: Phase 4
• First received: October 30, 2009
• Last updated: July 19, 2011
• Start date: July 2005
• Est. completion date: May 2007

Study information

• Verified date: July 2011
• Source: Montefiore Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

Research question: In adult emergency department (ED) patients to whom the attending ED physician has decided to administer intravenous opioid pain control:

1. What is the incidence of serious adverse events, defined as the use of naloxone, up to a total of 2 hours after infusion of 2 mg IV hydromorphone?

2. What is the incidence of other side effects (respiratory depression, hypotension, oxygen desaturation, nausea, vomiting, and pruritus) at 5, 15, 30 and 120 minutes post infusion of 2mg IV hydromorphone?

3. What is the speed of onset of 2 mg IV hydromorphone? This will be measured by asking the patient for his NRS pain score at 1, 2, 3, 4, and 5 minutes post infusion of 2 mg IV hydromorphone.

4. What is the incidence of administration of rescue medications?

5. For those patients who decline to enter the study, what are their reasons for refusal (e.g. fear of becoming addicted)? The investigators believe this is yet another barrier to providing adequate pain relief for patients with acute severe pain.

Description:

Introduction and Background: Pain is cited as the most frequent reason for visits to emergency departments (EDs) (McCaig, 2001). It can be estimated from the National Hospital Ambulatory Medical Care Survey, an annual survey of a representative sample of visits to US EDs, that there are 17 million visits per year to US EDs for specific complaints of pain, 29 million visits including "back symptoms" and "injuries not otherwise specified" as well as specific mentions of pain. However it is widely acknowledged that pain is seriously under-treated in the ED as well as in other health care settings (Ducharme, 1996; Selbst, 1990; Wilson, 1989). The concern regarding under-treatment is reflected in new standards for pain management developed by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) requiring assessment of pain at triage in the ED and referring to pain measurement as the "fifth vital sign" (Philips, 2000).

Proper pain management is a tremendous challenge to ED physicians as pain is not only a noxious experience but also a symptom of injury and disease that needs to be understood and appropriately treated. Further complicating pain management is the large interpersonal variability in pain perception and expression reflecting cultural, contextual, and individual differences between people. Reasons for under-treating pain include concern over side effects of opioids, perception of pain complaints as possible drug-seeking behavior, under-staffing, concern that analgesics will mask symptoms or delay early diagnosis and treatment, and contribute to risks of tolerance and dependence in vulnerable patients.

Morphine has long been considered the gold standard in pain control. Hydromorphone is another powerful opioid that has been used extensively for the management of post-operative pain and morphine-resistant cancer-related pain. A recent Cochrane review on the use of hydromorphone found 32 studies that focused on acute pain (Quigley, 2003). Of these 32 studies, only 9 involved intravenous forms of hydromorphone (Coda, 1997; Collins, 1996; Deutsch, 1968; Jasani, 1994; Liu, 1995; Mahler, 1975; Rapp, 1996; Searle, 1994; Urquhart, 1988). Of these 8 studies, 5 involved patient controlled analgesia, and only 1 study compared IV hydromorphone to IV morphine (Mahler, 1975). The Cochrane review concludes that there are substantial gaps in the understanding of the efficacy and potency of hydromorphone.

We have recently completed a study in non-elderly adult patients (IRB 04-08-225) that showed that weight-based IV hydromorphone provides better pain relief than weight-based IV morphine. This result was both statistically and clinically significant. We also demonstrated in this same study that IV hydromorphone has a faster onset and also provided statistically significant improvement in pain relief at 5 minutes as compared to IV morphine.

Although weight-based dosing of medications is common in pediatrics, most emergency physicians use whole integer amounts of pain medications. IV hydromorphone is more potent than IV morphine, so the dosages given are much smaller. We therefore wish to give a standard 2 mg dose of IV hydromorphone to all non-elderly adult patients weighing at least 150 lbs presenting to the ED with acute severe pain. We wish to examine the safety and speed of onset of hydromorphone using such a protocol.

Our general thought is that to develop more evidence based practice, we need to generate more practice based evidence. This study attempts to do this as it is practiced based and very practical. We wish to take the drug as it comes (2mg Dilaudid in an ampule) and use all of it, thus alleviating the need to waste the excess opioid (and alleviating the need to find a second person to witness the wasting). We also wish to use a weight cutoff that everyone can remember (150 lbs). We believe that this protocol will provide greater pain relief and help address the issue of inadequate pain treatment, or "oligoanalgesia", that is prominent in the literature (Sobel 2002, Wilson, 1989, Goldfrank 2000).

Finally, in our multiple studies of pain conducted in the ED, we have found a relatively high rate of refusal to receive pain medication. We think this may represent a component to the problem of oligoanalgesia that is widespread in the ED. We wish to investigate the reasons for patient refusal to receiving parental opioid medications (fear of addiction, side effects, etc).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 300
• Est. completion date: May 2007
• Est. primary completion date: May 2007
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 21 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Age greater than 21 years: Patients under the age of 21 are automatically triaged to the Children's Hospital at Montefiore Emergency Department, and hence cannot be enrolled in this study.

2. Age less than 65 years of age: Patients age 65 and over will be excluded in this study as the effects on opioids on the elderly may be different than in the non-elderly.

3. Pain with onset within 7 days: Pain within seven days is the definition of acute pain that has been used in ED literature.

4. ED attending physician's judgment that patient's pain warrants use of morphine: The factors that influence the decision to use parenteral opioids are complex and extensive. An approach that is commonly taken to address the issue of patient selection in drug trials is to use a specific condition (e.g., renal colic) or treatment (e.g., post-hysterectomy) that would generally be thought to be appropriately treated with an opioid analgesic, thereby eliminating individual judgment about eligibility for the study. However in order to assess the role of hydromorphone with the widest generalizability in the ED setting, we decided to enroll patients with a variety of diagnoses, all with a complaint of acute pain. Opioids are not an appropriate treatment for all patients who present with a complaint of pain (e.g., gastroenteritis, migraine). Therefore, unless there is a restriction to patients with a specific diagnosis, either a comprehensive list of diagnoses and situations in which opioids are indicated must be specified, or clinical judgment needs to be used. We have opted for the latter alternative.

The use of patients with a variety of diagnoses, and therefore heterogeneous painful stimuli, risks masking a treatment effect because of large inter-individual variability. There are several design and analytic factors (detailed below) that attenuate this risk: 1) a sufficiently large number of patients will be randomly assigned to each group so that the variety of painful stimuli will be equally distributed between treatment groups; 2) change in pain intensity and pain relief will be analyzed rather than absolute pain intensity or pain relief therefore reducing variability.

5. Normal mental status: In order to provide measures of pain experienced the patient needs to have a normal mental status. Orientation to person, place and time will be used as an indicator of sufficiently normal mental status to participate in the study.

Exclusion Criteria:

1. Prior use of methadone: the effect of methadone use on the perception of acute pain is unknown and suspected to be altered. We feel that the needs of patients on methadone may exceed the dosage ceiling of 2mg that will be used for this study. Similar to sickle cell patients and chronic cancer patients, patients on methadone usually require significantly higher doses of opioids to control their pain. Thus, we feel that it would be unethical to restrict the dose that this subset of patients can receive.

2. Use of other opioids or tramadol within past seven days: to avoid introducing bias related to opioid tolerance that may alter the response to the study medication thereby masking the medication's effect.

3. Prior adverse reaction to hydromorphone.

4. Chronic pain syndrome: frequently recurrent or daily pain for at least 3 months result in alteration in pain perception which is thought to be due to down-regulation of pain receptors. Examples of chronic pain syndromes include sickle cell anemia, osteoarthritis, fibromyalgia, migraine, and peripheral neuropathies.

5. Alcohol intoxication: the presence of alcohol intoxication as judged by the treating physician may alter perception, report, and treatment of pain.

6. SBP <90 mm Hg: Hydromorphone can produce peripheral vasodilation that may result in orthostatic hypotension or syncope.

7. Use of MAO inhibitors in past 30 days: MAOs have been reported to intensify the effects of at least one opioid drug causing anxiety, confusion and significant respiratory depression or coma.

8. C02 measurement greater than 46: In accordance with a similar study (04-12-360), three subsets of patients will have their CO2 measured using a handheld capnometer prior to enrollment in the study. If the CO2 measurement is greater than 46, then the patient will be excluded from the study. The 3 subsets are as follows:

1. All patients who have a history of COPD

2. All patients who report a history of asthma together with greater than a 20 pack-year smoking history

3. All patients reporting less than a 20 pack-year smoking history who are having an asthma exacerbation

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Pain

Intervention

Drug:
• Hydromorphone
2mg IV hydromorphone

Locations

Country	Name	City	State
United States	Montefiore Medical Center	Bronx	New York

Sponsors (1)

Lead Sponsor	Collaborator
Montefiore Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The incidence of a serious adverse event by 120 minutes post infusion, which is defined as the use of naloxone as a reversal agent.		120 minutes	Yes
Secondary	Respiratory depression: RR < 12 breaths per minute will be considered a less serious adverse event.		120 minutes	Yes
Secondary	Oxygen desaturation: The RAs will note the presence of oxygen desaturation, defined as a pulse oximeter reading less than 90% or a decrease of 5% or more from baseline, at the following time points: baseline, 1, 2, 3, 4, 5, 15, 30 and 120 minutes.		120 minutes	Yes
Secondary	Hypotension: Systolic BP less than 90 mg Hg will be counted as a less serious adverse event.		120 minutes	Yes
Secondary	Vomiting: Patients will be asked whether they vomited during the following time intervals: pre-baseline, baseline-5 minutes, 6 minutes to 15 minutes, 16 minutes to 30 minutes, and 31 minutes to 2 hours.		120 minutes	No
Secondary	Nausea: We will use the recently validated quantitative nausea visual analog scale (VAS) (Hendey 2005).		120 minutes	No
Secondary	Pruritis: Patients will be asked whether they experience pruritus at the following time intervals: pre-baseline, baseline-5 minutes, 6 minutes to 15 minutes, 16 minutes to 30 minutes, and 31 minutes to 2 hours.		120 minutes	No
Secondary	The RAs will assess the incidence of other adverse events such as falling by observation and by reviewing the nursing notes and chart, as well as by asking the patient's providers.		120 minutes	Yes
Secondary	Speed of onset of analgesia: Speed of onset of analgesia will be assessed by eliciting self-reported pain scores every minute for 5 minutes post infusion of hydromorphone.		120 minutes	No
Secondary	A numerical rating scale ranging from 0 = no pain, to 10 = worst pain possible will be used to measure self-reported pain.		120 minutes	No
Secondary	Speed of onset of analgesia will also be assessed by a 5-point pain relief scale.		120 minutes	No
Secondary	Patient Satisfaction Scale: Assessed using a 6-point patient satisfaction scale.		120 minutes	No
Secondary	Supplementary dose of opioid and non-opioid analgesics: The number of patients who receive supplementary pain medications as well as the total additional amount (mg) received.		120 minutes	No
Secondary	All medications administered to the patients and the time of administration will be recorded. Data from any patients who are given other opioids will be used up until the time the second opioid is administered		120 minutes	No