Hydromorphone for cancer pain New search for studies and content updated (no change to conclusions)

Abstract

Abstract 

Background 

This is an update of the original Cochrane Review first published in Issue 10, 2016. For people with advanced cancer, the prevalence of pain can be as high as 90%. Cancer pain is a distressing symptom that tends to worsen as the disease progresses. Evidence suggests that opioid pharmacotherapy is the most effective of these therapies. Hydromorphone appears to be an alternative opioid analgesic which may help relieve these symptoms.

Objectives 

To determine the analgesic efficacy of hydromorphone in relieving cancer pain, as well as the incidence and severity of any adverse events.

Search methods 

We searched CENTRAL, MEDLINE, Embase and clinical trials registers in November 2020. We applied no language, document type or publication status limitations to the search.

Selection criteria 

We included randomised controlled trials (RCTs) that compared hydromorphone with placebo, an alternative opioid or another active control, for cancer pain in adults and children. Primary outcomes were participant‐reported pain intensity and pain relief; secondary outcomes were specific adverse events, serious adverse events, quality of life, leaving the study early and death.

Data collection and analysis 

Two review authors independently extracted data. We calculated risk ratio (RR) and 95% confidence intervals (CI) for binary outcomes on an intention‐to‐treat (ITT) basis. We estimated mean difference (MD) between groups and 95% CI for continuous data. We used a random‐effects model and assessed risk of bias for all included studies. We assessed the evidence using GRADE and created three summary of findings tables.

Main results 

With four new identified studies, the review includes a total of eight studies (1283 participants, with data for 1181 participants available for analysis), which compared hydromorphone with oxycodone (four studies), morphine (three studies) or fentanyl (one study). All studies included adults with cancer pain, mean age ranged around 53 to 59 years and the proportion of men ranged from 42% to 67.4%. We judged all the studies at high risk of bias overall because they had at least one domain with high risk of bias.

We found no studies including children. We did not complete a meta‐analysis for the primary outcome of pain intensity due to skewed data and different comparators investigated across the studies (oxycodone, morphine and fentanyl).

Comparison 1: hydromorphone compared with placebo 

We identified no studies comparing hydromorphone with placebo.

Comparison 2: hydromorphone compared with oxycodone 

Participant‐reported pain intensity

We found no clear evidence of a difference in pain intensity (measured using a visual analogue scale (VAS)) in people treated with hydromorphone compared with those treated with oxycodone, but the evidence is very uncertain (3 RCTs, 381 participants, very low‐certainty evidence).

Participant‐reported pain relief

We found no studies reporting participant‐reported pain relief.

Specific adverse events

We found no clear evidence of a difference in nausea (RR 1.13 95% CI 0.74 to 1.73; 3 RCTs, 622 participants), vomiting (RR 1.18, 95% CI 0.72 to 1.94; 3 RCTs, 622 participants), dizziness (RR 0.91, 95% CI 0.58 to 1.44; 2 RCTs, 441 participants) and constipation (RR 0.92, 95% CI 0.72 to 1.19; 622 participants) (all very low‐certainty evidence) in people treated with hydromorphone compared with those treated with oxycodone, but the evidence is very uncertain.

Quality of life

We found no studies reporting quality of life.

Comparison 3: hydromorphone compared with morphine 

Participant‐reported pain intensity

We found no clear evidence of a difference in pain intensity (measured using the Brief Pain Inventory (BPI) or VAS)) in people treated with hydromorphone compared with those treated with morphine, but the evidence is very uncertain (2 RCTs, 433 participants; very low‐certainty evidence).

Participant‐reported pain relief

We found no clear evidence of a difference in the number of clinically improved participants, defined by 50% or greater pain relief rate, in the hydromorphone group compared with the morphine group, but the evidence is very uncertain (RR 0.99, 95% CI 0.84 to 1.18; 1 RCT, 233 participants; very low‐certainty evidence).

Specific adverse events

At 24 days of treatment, morphine may reduce constipation compared with hydromorphone, but the evidence is very uncertain (RR 1.56, 95% CI 1.12 to 2.17; 1 RCT, 200 participants; very low‐certainty evidence). We found no clear evidence of a difference in nausea (RR 0.94, 95% CI 0.66 to 1.30; 1 RCT, 200 participants), vomiting (RR 0.87, 95% CI 0.58 to 1.31; 1 RCT, 200 participants) and dizziness (RR 1.15, 95% CI 0.71 to 1.88; 1 RCT, 200 participants) (all very low‐certainty evidence) in people treated with hydromorphone compared with those treated with morphine, but the evidence is very uncertain.

Quality of life

We found no studies reporting quality of life.

Comparison 4: hydromorphone compared with fentanyl 

Participant‐reported pain intensity

We found no clear evidence of a difference in pain intensity (measured by numerical rating scale (NRS)) at 60 minutes in people treated with hydromorphone compared with those treated with fentanyl, but the evidence is very uncertain (1 RCT, 82 participants; very low‐certainty evidence).

Participant‐reported pain relief

We found no studies reporting participant‐reported pain relief.

Specific adverse events

We found no studies reporting specific adverse events.

Quality of life

We found no studies reporting quality of life.

Authors' conclusions 

The evidence of the benefits and harms of hydromorphone compared with other analgesics is very uncertain. The studies reported some adverse events, such as nausea, vomiting, dizziness and constipation, but generally there was no clear evidence of a difference between hydromorphone and morphine, oxycodone or fentanyl for this outcome.

There is insufficient evidence to support or refute the use of hydromorphone for cancer pain in comparison with other analgesics on the reported outcomes. Further research with larger sample sizes and more comprehensive outcome data collection is required.

Author(s)

Yan Li, Jun Ma, Guijun Lu, Zhi Dou, Roger Knaggs, Jun Xia, Sai Zhao, Sitong Dong, Liqiang Yang

Abstract

Plain language summary 

Hydromorphone for the treatment of cancer pain 

Background 

Over 75% of people with cancer experience pain. Around 30% to 50% of these people have moderate to severe pain, which can have a negative impact on daily life. Cancer pain is a distressing symptom that tends to worsen as the disease progresses. Hydromorphone may help relieve these symptoms. Cancer‐related pain is usually treated with medicines such as morphine, oxycodone, fentanyl or hydromorphone. This review looked at the benefits and harms of hydromorphone compared with other medicines.

Study characteristics 

In November 2020, we updated our searches for randomised controlled studies of hydromorphone compared with placebo, an alternative opioid or another active control. Randomised controlled studies are studies where people are randomly placed into different treatment groups. We found four studies that compared hydromorphone with oxycodone, three studies that compared hydromorphone with morphine and one study that compared hydromorphone with fentanyl.

Results 

This review includes eight studies (four new studies included in this updated version) with 1283 participants comparing hydromorphone with oxycodone, morphine or fentanyl in adults (aged 18 years and above) with moderate to severe cancer pain. None of the studies compared hydromorphone and placebo. None of the studies included children.

We found no differences in pain intensity scores between the different treatment groups and on average patients reported low levels of pain after opioid administration. Hydromorphone seemed to work as well as morphine, oxycodone and fentanyl. There were some side effects, such as nausea, vomiting, dizziness and constipation, but generally there was no clear difference between people taking hydromorphone and people taking morphine, oxycodone or fentanyl.

Certainty of the evidence 

We rated the certainty of the evidence from studies using four levels: very low, low, moderate or high. Very low‐certainty evidence means that we are very uncertain about the results. High‐certainty evidence means that we are very confident in the results. No results were rated as high certainty; we only identified very low‐certainty evidence for pain intensity, pain relief and side effects. These outcomes were rated as very low certainty because there were either few trials included with few participants, or due to other sources of bias, such as potential competing interests with the pharmaceutical industry.

Conclusions 

The studies did not provide enough high‐certainty evidence to draw firm conclusions; the evidence of the benefits and harms of hydromorphone compared with other medicines is very uncertain.

Author(s)

Yan Li, Jun Ma, Guijun Lu, Zhi Dou, Roger Knaggs, Jun Xia, Sai Zhao, Sitong Dong, Liqiang Yang

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

For people with cancer pain 

Based on data gathered from the eight included trials, it appears that hydromorphone has a similar effect on participant‐reported pain intensity as oxycodone, morphine and fentanyl for adults with moderate to severe cancer pain. There was no evident comparative difference in analgesic effect between hydromorphone and other opioids investigated in this review and the mean postintervention pain scores were generally below the threshold for 'no worse than mild pain' on all investigated treatments. There were several adverse events, but generally there was no difference between groups. In summary, there is no clear evidence of a difference between hydromorphone and oxycodone, morphine or fentanyl in adults with moderate to severe cancer pain. However, this finding should be applied with caution for our review included only eight studies, which had different designs and limited sample sizes. The evidence of the benefits and harms of hydromorphone compared with oxycodone, morphine and fentanyl is very uncertain. There were no data available for children or for some important outcomes such as quality of life.

For clinicians 

Based on eight included trials with different designs and limited number of participants, we found a lack of evidence to support a preference for hydromorphone over other opioid analgesics such as morphine, oxycodone and fentanyl. The treatment effect of hydromorphone appeared to be similar to that of the comparator drugs for adults with moderate to severe cancer pain. There were minor adverse events in all treatment groups and generally no clear evidence of a difference between groups. However, most of the outcome data were based on single randomised controlled trials with small sample sizes, thus the findings of the current review should be interpreted and applied with caution. We found no data for children. The insufficient evidence requires clinicians to balance potential benefits against potential adverse events on the merit of each individual case when recommending treatment in clinical practice.

For policy makers 

This review identified little evidence to support hydromorphone as the first‐, second‐ or third‐line treatment for cancer pain. However, evidence collated in the current review suggests hydromorphone has a similar analgesic effect as morphine, oxycodone and fentanyl, it can be considered as an alternative when other opioids result in excessive adverse events such as sedation and respiratory depression, and when people with cancer pain experience renal failure. We found no data for children. Included studies were conducted in high‐income countries, which may compromise the external validity of the review as some of the drugs investigated may have limited accessibility in some lower‐income countries. Finally, it is worth noting that findings from the current review are mainly based on small trials with different designs and limited sample size and some risk of bias, therefore, should be applied with caution.

Implications for research 

This review confirms a general lack of research in this subject area, with poor and inconsistent reporting of adverse events and low trial sizes. Wiffen 2017a suggest some core outcomes that can help decisions in clinical practice, for instance, the proportion of participants reporting no worse than mild pain on treatment by 14 days after start of treatment, Patient Global Impression of Change (PGIC) of much or very much improved. These outcomes are seldomly reported by the included studies. Future trials with significant numbers of participants (e.g. more than 200 per treatment arm) are needed to evaluate important outcomes of hydromorphone for the management of moderate to severe cancer pain in adults. Future research is encouraged to involve children and young adults to provide direct evidence in this population. Further adequately powered randomised controlled trials should use standardised tools or scales to measure pain as a primary outcome. More data on other secondary outcomes, as well as the comparative effect of a more comprehensive range of medications, would also be useful to enable the review to draw a more reliable and conclusive effect. Longer‐term toxicity data should be collected if possible.

Prevalence of sleep disturbance in people with cancer ranges from 24% to 95% (Graci 2005; Mercadante 2004), and is more common among females with cancer, older people, and people with depression or anxiety (Akechi 2007; Graci 2005). Therefore, we suggest that more attention is given to pain control for increasing quality of sleep and quality of life (Graci 2005; Kvale 2006), especially the effect of OROS (osmotic‐controlled release oral delivery system) hydromorphone for people with cancer pain with sleep disturbance. The absence of the outcome quality of life may indicate a research gap in the field. Further high‐quality randomised controlled trials are expected to define quality of life as an important outcome in trials.

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